Clinical trial NCT02896296
Conditions: Opioid Use Disorder Opioid-related Disorders
Sponsor: Indivior Inc.
Start date: 2016-08-17; Completion date: 2017-08-23
Enrollment: 208 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study is to provide ongoing treatment with RBP-6000 and safety monitoring for subjects who complete the RB-US-13-0003 study (NCT02510014) and for whom a new treatment venue has not been identified or arranged.

Detailed description:
This is a multi-center, open-label, RBP-6000 treatment extension study in which subjects who have completed the End of Study (EOS) procedures for study RB-US-13-0003 are eligible. EOS assessments completed at the RB-US-13-0003 EOS visit serve as part of the screening visit for this study. In addition, subjects were requested to complete a Columbia Suicide Severity Rating Scale (C-SSRS) baseline/screening survey and a medical history and height was obtained.

The informed consent may be shared with subjects up to 2 months prior to the RB-US-13-0003 EOS visit, however should not be signed until all assessments for the EOS visit have been completed.

On Day 1, eligible subjects receive a subcutaneous (SC) injection of RBP-6000 at a low or high dose based on the medical judgment of the investigator. After the injection, vital signs and the injection site were assessed. Prior to departing the site, subjects were also assessed for adverse events (AEs) and use of concomitant medications (ConMeds).

Subjects return to the site for monthly injection visits every 28 days (-2 / +7 days) for a total of up to 6 injections (participants were not required to complete all 6 injections). At each subsequent visit (Injections 2 through 6) the following procedures / assessments were performed : urine pregnancy test performed for all female subjects who are of childbearing potential before each injection; previous injection site assessed for potential reaction and evidence of attempts to remove the depot; vital signs collected pre and post each injection; RBP-6000 injection, urine drug screen (UDS); C-SSRS since last visit assessment, counseling (manual-guided behavioral therapy); use of ConMeds; local injection site grading, subject self-assessment of injection site pain (Injection Site Pain Visual Analog Scale \[VAS\]), assessment for adverse events (AEs).

Laboratory tests (hematology, chemistry and urinalysis) may be requested by the Investigator on an ad-hoc basis in order to assess for AEs.

A subject's alternative treatment options were assessed at least two months before EOS at each visit.

At EOS or early termination (ET), the following assessments were performed: urine pregnancy test performed for all female subjects who are of childbearing potential; vital signs; previous injection site assessed for potential reaction and evidence of attempts to remove the depot; UDS; C-SSRS since last visit assessment, counseling (manual-guided behavioral therapy); use of ConMeds; assessment for AEs; a brief physical exam; height and body weight were measured and a subject's body mass index (BMI) and waist-to-hip ratio calculated; laboratory tests (hematology, chemistry, urinalysis).

Subjects were to be contacted by telephone approximately 4 weeks after EOS/ET for a safety follow-up assessment of AEs and use of ConMeds.

Arms: arm 1: On Day 1 of the study all eligible subjects received a single subcutaneous (SC) injection of RBP-6000. Participants returned to the site for monthly injection visits every 28 days (-2/+7 days) for a total of up to 6 injections. Participants were not required to complete all 6 injections and could choose to terminate from the study at any time.

For each injection, participants could receive either a dose of 100 mg RBP-6000 or 300 mg RBP-6000, based on the medical judgement of the investigator.
Interventions: intervention 1: RBP-6000
Intervention descriptions: intervention 1: Monthly injections subcutaneously on alternate sides of participant's abdomen. Dose could be adjusted from 100 mg to 300 mg (or the reverse) based on the medical judgment of the investigator.

Protocol documents:
Prot_000.pdf: 
NCT02896296 
 
Study Number:  INDV-6000-301 
 
Title:  An Open-Label, Depot Buprenorphine (RBP-6000) Treatment Extension 
Study in Subjects With Opioid Use Disorder 
 
Protocol Date:  30 September 2016 


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Clinical Study Protocol: INDV-6000-301
Study Title:
An Open-Label, Depot Buprenorphine (RBP-6000) Treatment 
Extension Study in Subjects with Opioid Use Disorder
Study Number:
INDV-6000-301
Study Phase:
3
Product Name:
RBP-6000
IND Number:
107,607
Indication:
Treatment of Opioid Use Disorder
Investigators:
Multicenter
Sponsor:
Indivior Inc.
10710 Midlothian Turnpike, Suite 430
Richmond, VA 23235
Sponsor Contact:
Head Late Stage Development, Global Clinical Development
Medical Monitor:
Scientific Research Fellow, Global Clinical Development
Date
Original Protocol:
24 June 2016
Amendment 1
30 September 2016
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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Clinical Study Protocol: INDV-6000-301
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SYNOPSIS
Sponsor: 
Indivior Inc.
Name of Finished Product:
RBP-6000, 18% buprenorphine sterile solution for subcutaneous (SC) injection
Name of Active Ingredient:
Buprenorphine
Name of Inactive Ingredient: 
ATRIGEL® Delivery System
Study Title:
An Open-Label, Depot Buprenorphine (RBP-6000) Treatment Extension Study in Subjects with 
Opioid Use Disorder
Study Number:
INDV-6000-301
Study Phase: Phase 3
Study Objective:
To provide ongoing treatment with RBP-6000 and safety monitoring for subjects who complete 
the RB-US-13-0003 study and for whom a new treatment venue has not been identified or 
arranged.
Study Design:
This is a multicenter, open-label, RBP-6000 treatment extension study in which approximately 
300 subjects diagnosed with Opioid Use Disorder (OUD) will be enrolled. Enrollment is defined 
as the first dose of RBP-6000 administered for this study. Only subjects who have completed the 
End of Study (EOS) procedures for Study RB-US-13-0003, have signed the INDV-6000-301 
informed consent form (ICF), and meet all the enrollment criteria may be considered for 
inclusion in this study.
The institutional review board (IRB) approved ICF may be shared with the potential subject up 
to 2 months before EOS Visit for Study RB-US-13-0003 in order to discuss this study as a 
possible treatment option. However, the ICF for Study INDV-6000-301 must not be signed until 
all assessments for the RB-US-13-0003 EOS Visit are complete.
The RB-US-13-0003 EOS assessments completed at the EOS Visit will serve as part of the 
screening assessments for this study. In addition, medical history will be collected, height 
measured, and subjects will be requested to complete a Columbia Suicide Severity Rating Scale 
(C-SSRS) baseline survey. The same-day Study RB-US-13-0003 EOS Visit / INDV-6000-301 
Screening Visit will also be considered Day 1 of this study.
On Day 1, eligible subjects will receive a subcutaneous (SC) injection of RBP-6000. For each 
injection, subjects may receive either a dose of 100 mg RBP-6000 or 300 mg RBP-6000, based 
on the medical judgment of the Investigator. Following RBP-6000 injection, vital signs and the 
injection site will be assessed. The injection site will be assessed by the site for pain, tenderness, 
warmth, itching, erythema, inflammation or swelling, and bruising using a 5-point severity scale 


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(the Injection Site Grading Scale). In addition, the subject will assess their own injection site 
pain using a visual analog scale (VAS) (referred to as the Injection Site Pain VAS).  Before 
departing the site, the subject will also be assessed for adverse events (AEs) and use of 
concomitant medications. 
Subjects will not be permitted to receive supplemental buprenorphine during the RBP-6000 
treatment period (Day 1 to EOS/ET Visit).  Subjects who require supplemental buprenorphine 
pharmacotherapy during the RBP-6000 treatment period will be withdrawn from the study and 
referred for appropriate treatment.
Subjects will return to the site for monthly injection visits every 28 days (-2 / +7 days) for a total 
of up to 6 injections. Subjects are not required to complete all 6 injections and may choose to 
“early terminate” (ET) the study at any time.
At each subsequent visit (Injection Visits 2 through 6) the following procedures and assessments 
will be performed:   urine pregnancy test for all female subjects who are of childbearing potential 
before each injection; evaluation of previous injection site for potential reaction and evidence of 
attempts to remove the depot; collection of vital signs pre- and post-injection; RBP-6000 
injection, urine drug screen (UDS); C-SSRS since last visit, counseling (manual-guided 
behavioral therapy); local injection site grading; subject self-assessment of injection site pain 
(Injection Site Pain VAS); use of concomitant medications; and assessment for AEs. Laboratory 
tests (hematology, chemistry and urinalysis) may be requested by the Investigator on an ad-hoc 
basis as necessary to further examine any AEs. 
Alternative treatment options should be assessed at least two months before EOS at each visit, 
however it is recommended where possible to assess at every visit. 
At the EOS/ET Visit, the following procedures and assessments will be performed: 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; vital sign 
measurements; UDS; C-SSRS since last visit, counseling (manual-guided behavioral therapy); 
use of concomitant medications; assessment for AEs; brief physical exam; height and body 
weight measurement (to determine a subject’s body mass index [BMI]); hip and waist 
circumference measurement (to determine a subject’s hip-to-waist ratio); and laboratory tests 
(hematology, chemistry, urinalysis). 
Approximately 4 weeks after EOS/ET Visit, all subjects should be contacted by telephone for a 
safety follow-up assessment of AEs and use of any concomitant medications. 
Study Population:
All subjects who completed the RB-US-13-0003 study may be eligible to enroll into this study. 
Approximately 300 subjects will be enrolled. 
Test Product, Dose, and Mode of Administration:
300 mg buprenorphine in RBP-6000, subcutaneous injection
100 mg buprenorphine in RBP-6000, subcutaneous injection
Duration of Study Treatment:
This will be a multiple-dose study, with the first investigational product administration 
(RBP-6000) occurring on Study Day 1. The expected duration of participation for each subject is 
up to approximately 29 weeks, consisting of a 25-week, open-label treatment period and a safety 


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follow-up phone call at 4 weeks after the EOS/ET Visit.
Safety Assessments:
Safety will be assessed throughout the entire study on the basis of the following: AEs, serious 
adverse events (SAE)s, discontinuations from study due to AEs; local injection site tolerability 
(based on injection site grading); injection site pain using a subject-reported VAS; suicidality 
using the C-SSRS, use of concomitant medications; clinically significant changes in clinical 
laboratory results; vital sign measurements; physical examination findings; and measurements of 
body weight, height, waist and hip circumference (for calculation of BMI and abdominal fat 
measurement [waist-to-hip ratio]).
Statistical Methods:
A Statistical Analysis Plan (SAP) will be finalized before database lock occurs.  The SAP will 
provide further details regarding the definition of analysis endpoints, data handling rules, and the 
statistical methodology to be used to address all study objectives.  The SAP will also include 
formats for the summary and analysis tables, listings, and graphical displays.
Determination of Sample Size:
Approximately 300 subjects who completed Study RB-US-13-0003 will be enrolled into this 
study.
Safety Analyses:
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the C-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; physical examination results; body weight, height, BMI, and abdominal fat 
measurement (waist-to-hip ratio). Safety variables will be described using descriptive statistics 
for continuous endpoints (e.g., mean, median, standard deviation (SD), minimum and maximum) 
and frequency counts with percentages for discrete endpoints.
Baseline is defined as the value collected at Screening.  No imputation of missing values will be 
performed.
Date of Original Protocol: 24 June 2016
Date of Protocol Amendment 1:  30 September 2016


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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
LIST OF IN-TEXT TABLES ....................................................................................................8
LIST OF IN-TEXT FIGURES...................................................................................................8
LIST OF APPENDICES............................................................................................................8
LIST OF ABBREVIATIONS....................................................................................................9
1
INTRODUCTION ...........................................................................................................11
1.1
Background Information........................................................................................11
1.2
Rationale for Dose Selection .................................................................................14
1.3
Known and Potential Risks and Benefits...............................................................14
1.4
Good Clinical Practice...........................................................................................14
2
STUDY OBJECTIVE......................................................................................................16
3
INVESTIGATIONAL PLAN..........................................................................................17
3.1
Overall Study Design and Plan..............................................................................17
3.2
Rationale for Study Design....................................................................................20
3.3
Study Duration and Dates......................................................................................20
4
STUDY POPULATION SELECTION ...........................................................................21
4.1
Study Population....................................................................................................21
4.2
Inclusion Criteria ...................................................................................................21
4.3
Exclusion Criteria ..................................................................................................21
5
STUDY TREATMENTS.................................................................................................23
5.1
Description of Treatment.......................................................................................23
5.2
Treatments Administered.......................................................................................23
5.3
Selection and Timing of Dose for Each Subject....................................................23
5.4
Method of Assigning Subjects to Treatment Groups.............................................23
5.5
Blinding..................................................................................................................24
5.6
Restrictions ............................................................................................................24
5.7
Dosing Compliance................................................................................................24
5.8
Packaging and Labeling.........................................................................................24
5.9
Product Quality Complaints...................................................................................24
5.10
Storage and Accountability....................................................................................24
5.11
IMP Retention at Study Site ..................................................................................25
6
STUDY PROCEDURES .................................................................................................26
6.1
Medical History .....................................................................................................26
6.2
Physical Examination.............................................................................................26
6.3
Body Mass Index and Hip-to-Waist Ratio.............................................................26
6.4
Vital Signs..............................................................................................................27


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6.5
Clinical Laboratory Tests.......................................................................................27
6.5.1
Laboratory Parameters.................................................................................27
6.5.2
Sample Collection, Storage, and Shipping ..................................................28
6.5.3
Reference Ranges.........................................................................................29
6.5.4
Laboratory Results Review..........................................................................29
6.6
Suicidality Assessments.........................................................................................29
6.7
Local Injection Site Tolerability............................................................................29
6.7.1
Injection Site Evaluation..............................................................................29
6.7.2
Injection Site Grading..................................................................................30
6.7.3
Injection Site Pain Visual Analog Scale (VAS) ..........................................30
6.8
Pharmacokinetic Assessments ...............................................................................30
6.9
Adverse Events Assessments.................................................................................30
6.9.1
Adverse Event Definition ............................................................................30
6.9.2
Treatment-Emergent Adverse Event Definition ..........................................31
6.9.3
Performing Adverse Events Assessments....................................................31
6.9.4
Timing..........................................................................................................31
6.9.5
Severity ........................................................................................................32
6.9.6
Relationship .................................................................................................32
6.9.7
Expectedness................................................................................................32
6.9.8
Clinical Significance....................................................................................33
6.9.9
Clinical Laboratory Adverse Events............................................................33
6.9.10
Serious Adverse Events ...............................................................................33
6.9.11
Serious Adverse Event Definition ...............................................................33
6.9.11.1
Suspected Unexpected Serious Adverse Event Definition................33
6.9.11.2
Reporting Serious Adverse Events ....................................................34
6.9.12
Pregnancy.....................................................................................................34
6.10
Concomitant Medication Assessments ..................................................................35
6.10.1
Prohibited Concomitant Medications ..........................................................35
6.11
Counseling/Behavioral Therapy ............................................................................36
6.12
Removal of Subjects from the Study .....................................................................36
6.12.1
Early Removal of RBP-6000 .......................................................................36
6.12.2
Stopping Rules.............................................................................................37
6.12.3
Lost to Follow-up.........................................................................................37
6.12.4
Screen Failures.............................................................................................37
6.13
Other Study Procedures .........................................................................................37
6.13.1
Unscheduled Visits ......................................................................................37
6.14
Appropriateness of Measurements.........................................................................38
7
STUDY ACTIVITIES .....................................................................................................39
8
QUALITY CONTROL AND ASSURANCE .................................................................40


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8.1
Quality Control ......................................................................................................40
8.2
Quality Assurance..................................................................................................40
9
PLANNED STATISTICAL METHODS ........................................................................41
9.1
General Considerations..........................................................................................41
9.2
Determination of Sample Size ...............................................................................41
9.3
Analysis Populations..............................................................................................41
9.4
Demographics and Baseline Characteristics..........................................................41
9.5
Primary Analysis....................................................................................................41
9.5.1.1
Adverse Events ..................................................................................42
9.5.1.2
Laboratory Data .................................................................................42
9.5.1.3
Vital Signs..........................................................................................42
9.5.1.4
Other Variables Related to Safety......................................................42
9.6
Handling of Missing Data......................................................................................43
9.7
Subjects Who Withdraw from the Study ...............................................................43
9.8
Interim Analyses ....................................................................................................43
10
ADMINISTRATIVE CONSIDERATIONS....................................................................44
10.1
Investigators and Study Administrative Structure.................................................44
10.1.1
Sponsor ........................................................................................................44
10.1.2
Investigational Site(s) ..................................................................................44
10.1.3
Laboratories .................................................................................................44
10.2
Institutional Review Board Approval....................................................................44
10.3
Ethical Conduct of the Study.................................................................................44
10.4
Subject Informed Consent......................................................................................45
10.5
Subject Confidentiality ..........................................................................................45
10.6
Study Monitoring...................................................................................................45
10.6.1
Study and Site Closure.................................................................................46
10.7
Case Report Forms and Study Records .................................................................46
10.8
Data Monitoring Committee..................................................................................47
10.9
Protocol Deviations................................................................................................47
10.10 Access to Source Documentation ..........................................................................47
10.11 Data Generation and Analysis ...............................................................................48
10.11.1
Data Collection and Data Management.......................................................48
10.11.2
Database Quality Assurance ........................................................................48
10.12 Retention of Data...................................................................................................48
10.13 Financial Disclosure...............................................................................................48
10.14 Publication and Disclosure Policy .........................................................................49
11
REFERENCE LIST .........................................................................................................50


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LIST OF IN-TEXT TABLES
Table 1
Summary of Completed RBP-6000 Clinical Studies...................................12
Table 2
List of Laboratory Tests...............................................................................28
LIST OF IN-TEXT FIGURES
Figure 1
Study Overview ...........................................................................................19
Figure 2
Injection Locations.......................................................................................54
LIST OF APPENDICES
Appendix 1
Schedule of Events.............................................................................51
Appendix 2
IMP Preparation, Administration, and Depot Removal Instructions.53
Appendix 3
Prohibited Cytochrome P450 Inhibitors and Inducers.......................56
Appendix 4
Columbia Suicide Severity Rating Scale (C-SSRS) --
Baseline/Screening Version.........................................................................................58
Appendix 5
Columbia Suicide Severity Rating Scale (C-SSRS) --  Since Last 
Visit Version
60
Appendix 6
Injection Site Grading Scale ..............................................................62
Appendix 7
Injection Site Pain Visual Analog Scale............................................63
Appendix 8
Elevated Liver Function Tests ...........................................................64
Appendix 9
Sponsor Signatures.............................................................................66
Appendix 10
Investigator’s Signature .....................................................................67


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Clinical Study Protocol: INDV-6000-301
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LIST OF ABBREVIATIONS
AE
Adverse event
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase
AST
Aspartate transaminase
BMI
Body mass index
BUN
Blood urea nitrogen
CRA
Clinical Research Associate
C-SSRS
Columbia Suicide Severity Rating Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
eCRF
Electronic case report form
ECG
Electrocardiogram
EOS
End of study
ET
Early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HDL
High-density lipoprotein
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation 
IM
Intramuscular
IMP
Investigational medicinal product
IRB
Institutional review board
IV
Intravenous
IWRS
Interactive web response system
LDL
Low-density lipoprotein 
NMP
N-methyl-2-pyrrolidone
OTC
Over-the-counter
OUD
Opioid Use Disorder


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PK
Pharmacokinetic
PLGH
Poly (DL-lactide-co-glycolide) 
QA
Quality Assurance
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Standard deviation
SL 
Sublingual
SOE
Schedule of events
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment-emergent adverse event
UDS
Urine Drug Screen
US/USA
United States/United States of America
VAS
Visual analog scale
WHO
World Health Organization 


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1
INTRODUCTION
Opioid use disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5; American Psychiatric Association 2013), is a neurobehavioral syndrome 
characterized by the repeated, compulsive seeking or use of an opioid despite adverse social, 
psychological, and/or physical consequences.  Opioid use disorder (OUD) is a medical illness 
with high costs to individuals, families, and society.  Direct and indirect costs attributable to 
illicit drug use are estimated in 3 principal areas: crime, productivity, and health (US Department 
of Justice, Economic Impact of Illicit Drug Use on American Society, 2011). These high costs 
have prompted researchers to seek new medications and treatment strategies for opioid 
dependence aiming to reduce the use of prescription or illicit opioids.  
Buprenorphine, a mu-opioid receptor partial agonist and kappa-opioid receptor antagonist, is one 
such medication that has had a significant role in expanding access to effective opioid 
dependence treatment. Buprenorphine has been approved for use in the treatment of opioid 
dependence in a number of countries worldwide. Buprenorphine has been reported to have a 
lower physical dependence liability than pure agonist analgesics such as morphine, and at a 
sufficient dose, it can suppress opioid withdrawal signs and symptoms for at least 24 hours.  
Limited euphoric and respiratory depressant effects have led to its therapeutic use as a 
pharmacotherapy for opioid use disorder.
The sponsor is currently developing a buprenorphine depot (RBP-6000), which is a 
subcutaneously injected for the treatment of OUD.  It contains buprenorphine in the ATRIGEL 
Delivery System and provides sustained plasma levels of buprenorphine over a minimum of 28 
days (RBP-6000 IB).  
The ATRIGEL Delivery System is a sterile, polymeric solution of a biodegradable 
poly DL-lactide-co-glycolide (PLGH) copolymer, dissolved in the water-miscible, biocompatible 
solvent N-methyl-2-pyrrolidone (NMP).  The ATRIGEL Delivery System is well characterized.  
It is currently used in 7 approved products worldwide, including 4 ELIGARD® products 
(subcutaneous [SC] depot formulations of leuprolide acetate), ATRIDOX® (doxycycline hyclate 
applied to the periodontal pocket), the ATRISORB® Bioabsorbable Guided Tissue Regeneration 
Barrier for periodontal application, and the ATRISORB-D Barrier (ATRISORB with 
doxycycline) for periodontal guided tissue regeneration.
1.1
Background Information
To date, there have been 4 clinical studies completed using RBP-6000 (Table 1).


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Table 1
Summary of Completed RBP-6000 Clinical Studies
Study
Study Title
IMP
(Dose)
Most Common
AE(s) Possibly Related to 
Study Drug
Other Safety
RB-US-10-0011
A Single-Dose, Open-Label Study 
of Depot Buprenorphine (RBP-
6000) in Opioid Dependent 
Individuals
RBP-6000
(20 mg)
Drug withdrawal syndrome
Injection site pain
Rebound hypertension
Constipation
Headache
Injection site warmth
Respiratory rate increased
No clinically significant trends in vital signs, 
ECGs, clinical laboratory tests, or physical 
examinations.
No deaths or SAEs related to treatment and 
no subjects discontinued due to an AE.
RB-US-11-0020
A Multicenter, Open-Label, Single 
Ascending-Dose Study to 
Evaluate the Safety, Tolerability, 
and Pharmacokinetics of Depot 
Buprenorphine (RBP-6000) in 
Opioid-Dependent Subjects
RBP-6000
(50 mg, 
100 mg, and 
200 mg)
Drug withdrawal syndrome
Constipation
Diarrhea
Nausea
Injection site pain
No clinically significant trends in vital signs, 
ECGs, clinical laboratory tests, or physical 
examinations.
No deaths or SAEs related to treatment and 
no subjects discontinued due to an AE.
RB-US-12-0005
An Open-Label, Multicenter, 
Multiple Dose Study of the Safety, 
Tolerability, Pharmacokinetics, 
Efficacy Markers, and Opioid 
Receptor Availability of 
Subcutaneous Injections of Depot 
Buprenorphine (RBP-6000) in 
Treatment Seeking Opioid 
Dependent Subjects
RBP-6000
(50 mg, 
100 mg, 
200 mg, and 
300 mg)
Drug withdrawal syndrome
Vomiting
Constipation
Musculoskeletal pain
Anxiety
Upper Respiratory Tract
Infection
Liver function test abnormal
No clinically significant trends in 
hematology, serum chemistry, urinalysis, 
vital signs, or ECGs.
There were 9 SAEs during the study; 3 
subjects withdrawn due to SAEs; 8 subjects 
withdrawn from the study due to a TEAE. 
None of the above events were considered 
related to study medication.
RB-US-13-0002
A Multiple-Dose Study of 
Blockade of Subjective Opioid 
Effects, Pharmacokinetics, and 
Safety of Subcutaneous Injections 
of Depot Buprenorphine (RBP-
6000) in Subjects with Opioid Use 
Disorder
RBP-6000
(300 mg)
Drug withdrawal syndrome
Headache
Anxiety
Constipation
Liver function test abnormal
Injection site reaction
No clinically significant trends in 
hematology, serum chemistry, urinalysis, 
vital signs, and ECGs.
No deaths, no SAEs, and no withdrawals 
from the study due to a TEAE.
AE = Adverse Event; ECG = Electrocardiogram; IMP = Investigational medicinal product; SAE = Serious adverse event; TEAE = Treatment-emergent 
adverse event.


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In summary, doses of 50, 100, 200 and 300 mg RBP-6000 have been administered to male and 
female subjects and have been safe and well tolerated.  (RBP-6000 IB).  
A population pharmacokinetic (PK) model was developed to characterize the disposition of 
buprenorphine and norbuprenorphine following SC injection of RBP-6000 (Nasser 2014).  The 
population PK model accurately predicted the PK data after repeated doses of RBP-6000 in the 
multiple ascending dose study (RB-US-12-0005) and in the opioid blockade study (RB-US-13-
0002). Another population PK/PD model was developed to characterize the link between 
buprenorphine plasma concentration and mu opioid receptor occupancy (Nasser 2014).  The 
model simulations indicated that the desired 70% mu opioid receptor occupancy may be 
achieved after multiple doses of 200 mg of RBP-6000.  The 300 mg dose was considered to be a 
full opioid blockade dose.
There are currently 2 studies in the process of being completed and 1 study is ongoing:

RB-US-13-0006 – A Single-Center, Randomized, Open-Label, Single-Dose Study to 
Evaluate the Pharmacokinetics, Safety, and Tolerability of Depot Buprenorphine (RBP-
6000) Using Poly (DL-lactide-co-glycolide) Polymer of Two Different Molecular 
Weights (Low and High Molecular Weights as Test Treatments) in Comparison to 
Intermediate Molecular Weight (Reference Treatment) in Treatment-Seeking Subjects 
with Opioid Use Disorder.  [Study Status: Study has concluded/analysis in progress]
o
An investigational Phase I PK study evaluating the PK, safety, and tolerability of 
300 mg RBP-6000 using different molecular weights of the PLGH within the 
ATRIGEL delivery system, in Treatment-Seeking Subjects with OUD. 

RB-US-13-0001 - A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study 
To Assess the Efficacy, Safety, and Tolerability of Multiple Subcutaneous Injections of 
Depot Buprenorphine (RBP-6000 [100 mg and 300 mg]) Over 24 Weeks in Treatment-
Seeking Subjects with Opioid Use Disorder.  [Study Status: Study has concluded/analysis 
in progress]
o
A Phase III double-blind, placebo controlled efficacy study. The study is 
assessing the Efficacy, Safety, and Tolerability of 6 Subcutaneous Injections of 
RBP-6000 [100 mg and 300 mg] (or placebo) in approximately 500 treatment-
seeking subjects with OUD. Subjects who successfully completed this study were 
permitted to enroll in study RB-US-13-0003, if eligible. 

RB-US-13-0003 - An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With Opioid Use Disorder. 
[Study Status: Ongoing/analysis is pending]
o
A Phase III, open-label, long-term safety and tolerability Study of RBP-6000 in 
approximately 600 treatment-seeking subjects with OUD.  Subjects in this study 
will be dosed with a maximum of 12 injections of RBP-6000 (if enrolled directly 


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onto this study), and a maximum of 6 injections if enrolled from study RB-US-13-
0001. 
1.2
Rationale for Dose Selection
The doses proposed in this study are 100 mg RBP-6000 and 300 mg RBP-6000, which are the 
doses subjects are currently receiving in the RB-US-13-0003 study. These doses were chosen in 
the RB-US-13-0001 and RB-US-13-0003 studies as modeling and simulation (Nasser 2014) 
demonstrated that the 300 mg SC dose is an appropriate dose to assess for efficacy. The 100 mg 
RBP-6000 dose is provided because it is recognized that some individuals may need or desire 
lower dosages. 
Doses of RBP-6000 may be adjusted up or down (to either 100 mg or 300 mg) throughout the 
course of the study based on the medical judgment of the Investigator. 
1.3
Known and Potential Risks and Benefits
The AE profile of buprenorphine is well-characterized; commonly reported effects include 
constipation, nausea, vomiting, and headache.  Buprenorphine is approved for use by various 
routes of administration (e.g., sublingual [SL], intramuscular [IM], intravenous [IV], 
transdermal, and rectal).
Studies of buprenorphine receptor binding in human subjects have consistently and reproducibly 
established that buprenorphine is a highly lipophilic, mu-opioid receptor partial agonist with 
slow receptor association and dissociation kinetics.  Buprenorphine has an improved safety 
profile relative to mu-opioid receptor full agonists due to its partial agonist properties.  These 
attributes of buprenorphine allow it to perform well as substitution therapy for opioid-dependent 
individuals over short-term and long-term durations.  The experiments used to establish the 
binding profile of buprenorphine were consistent across differing parenteral routes of 
administration (IV, IM, and SL); therefore, RBP-6000 is expected to perform similarly when 
administered as a SC depot in the ATRIGEL Delivery System.
The purpose of this study (INDV-6000-301) is to continue to provide up to an additional 6 
injections of RBP-6000 for those subjects who have completed study RB-US-13-0003 and 
where a new treatment venue has not yet been identified, or arranged while ensuring their use of 
the product is monitored for safety. 
A sustained-release formulation of buprenorphine using the ATRIGEL Delivery System offers a 
number of potential benefits relative to shorter-acting formulations, including improved subject 
compliance, reduced diversion and misuse, as well as a reduced risk to subjects, their families, 
and the community.
1.4
Good Clinical Practice 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the Sponsor, designees and Investigator abide by Good 
Clinical Practice (GCP) as described in 21CFR parts 50, 54, 56, and 312 as well as in the 


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International Council for Harmonisation (ICH) Guidelines Topic E6 (R1): Guideline for Good 
Clinical Practice”. The study will also be carried out in accordance with local legal and 
regulatory requirements.


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2
STUDY OBJECTIVE
To provide ongoing treatment with RBP-6000 and safety monitoring for subjects who complete 
the RB-US-13-0003 study and for whom a new treatment venue has not been identified or 
arranged.


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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
This is a multicenter, open-label, RBP-6000 treatment extension study in which approximately 
300 subjects diagnosed with Opioid Use Disorder (OUD) will be enrolled. Enrollment is defined 
as the first dose of RBP-6000 administered for this study. Only subjects who have completed the 
End of Study (EOS) procedures for Study RB-US-13-0003, have signed the INDV-6000-301 
informed consent form (ICF), and meet all the enrollment criteria may be considered for 
inclusion in this study.  
The IRB approved ICF may be shared with the potential subject up to 2 months before EOS Visit 
for Study RB-US-13-0003 in order to discuss this study as a possible treatment option. However, 
the ICF for Study INDV-6000-301 must not be signed until all assessments for the RB-US-13-
0003 EOS Visit are complete.
The RB-US-13-0003 EOS assessments completed at the EOS Visit will serve as part of the 
screening assessments for this study. In addition, medical history will be collected, height 
measured, and the subjects will be requested to complete a Columbia Suicide Severity Rating 
Scale (C-SSRS) baseline/screening survey. The same-day Study RB-US-13-0003 EOS Visit / 
INDV-6000-301 Screening Visit will also be considered Day 1 of this study.
On Day 1, eligible subjects will receive a subcutaneous (SC) injection of RBP-6000. For each 
injection, subjects may receive either a dose of 100 mg RBP-6000 or 300 mg RBP-6000, based 
on the medical judgment of the Investigator. Following RBP-6000 injection, vital signs and the 
injection site will be assessed. The injection site will be assessed for pain, tenderness, warmth, 
itching, erythema, inflammation or swelling, and bruising using a 5-point severity scale 
(Injection Site Grading Scale). In addition, the subject will assess their own injection site pain 
using a visual analog scale (VAS) (referred to as the Injection Site Pain VAS). Before departing 
the site, the subject will also be assessed for adverse events (AEs) and use of concomitant 
medications.
Subjects will not be permitted to receive supplemental buprenorphine during the RBP-6000 
treatment period (Day 1 to EOS/ET Visit).  Subjects who require supplemental buprenorphine 
pharmacotherapy during the RBP-6000 treatment period will be withdrawn from the study and 
referred for appropriate treatment.  [Note: If subjects complete their EOS/ET Visit and a new 
treatment venue for them has not been identified, the Investigator may provide the subject further 
buprenorphine treatment or another appropriate treatment according to their own medical 
judgement.]
Subjects will return to the site for monthly injection visits every 28 days (-2 / +7 days) for a total 
of up to 6 injections. Subjects are not required to complete all 6 injections and may choose to 
“early terminate” (ET) the study at any time.
At each subsequent visit (Injection Visits 2 through 6) the following procedures and assessments 
will be performed:   urine pregnancy test for all female subjects who are of childbearing potential 
before each injection; evaluation of previous injection site for potential reaction and evidence of 
attempts to remove the depot; collection of vital signs pre- and post-injection; RBP-6000 
injection; urine drug screen (UDS); C-SSRS since last visit assessment, counseling (manual-


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guided behavioral therapy); local injection site grading; subject self-assessment of injection site 
pain (Injection site Pain VAS); use of concomitant medications; and assessment for AEs. 
Laboratory tests (hematology, chemistry and urinalysis) may be requested by the Investigator on 
an ad-hoc basis as necessary to further examine any AEs. 
Alternative treatment options should be assessed at least two months before EOS at each visit, 
however it is recommended where possible to assess at every visit.
At the EOS/ET Visit, the following procedures and assessments will be performed: 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; vital sign 
measurements; UDS; C-SSRS “since last visit” assessment, counseling (manual-guided 
behavioral therapy); use of concomitant medications; assessment for AEs; brief physical exam; 
height and body weight measurement (to determine a subject’s BMI); hip and waist 
circumference (to determine a subject’s hip-to-waist ratio); and laboratory tests (hematology, 
chemistry, urinalysis). 
Approximately 4 weeks after EOS/ET Visit, all subjects should be contacted by telephone for a 
safety follow-up assessment of AEs and use of any concomitant medications.
A schematic depicting the study design is presented in Figure 1.  A complete list of procedures 
and assessments for subjects is in the Schedule of Events (SOE) in Appendix 1.


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Figure 1
Study Overview
Note: RB-US-13-0003 EOS / Screening and RBP-6000 Injection 1 / Week 1 occurs on the same 
day (Day 1).


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3.2
Rationale for Study Design
The purpose of this study is to provide up to an additional 6 injections of RBP-6000 for those 
subjects who have completed the RB-US-13-0003 study and for whom a new treatment venue 
has not yet been identified or arranged while ensuring their use of the product is monitored for 
safety. The study design includes only monthly visits with additional safety assessments while 
the long term safety and tolerability of RBP-6000 are being studied. 
3.3
Study Duration and Dates
This will be a multiple-dose study, with the first IMP administration (RBP-6000) on Day 1. The 
expected maximum duration of participation for subjects is up to approximately 29 weeks 
consisting of a maximum 25-week open-label treatment period, and a safety follow-up phone call 
at 4 weeks after the EOS/ET Visit.
Subjects who receive at least 1 dose of RBP-6000 and discontinue the trial for any reason will be 
required to complete the EOS/ET Visit and the safety follow-up telephone call.


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4
STUDY POPULATION SELECTION
4.1
Study Population
Approximately 300 subjects will be enrolled into this study. The study population will consist of 
individuals diagnosed with OUD who are seeking treatment for opioid use disorder, and who 
have completed the EOS for RB-US-13-0003 study. 
4.2
Inclusion Criteria
Subjects who have successfully completed Study RB-US-13-0003 EOS assessments, which will 
serve as screening for this study. In addition, only the following criteria must be met to be 
enrolled in this study:
1. Provide written consent to participate in this study.
2. Completed the End of Study Visit for the RB-US-13-0003 study. 
3. Be considered eligible in the medical judgment of the Investigator.
4. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to ICF) must have a negative pregnancy 
test prior to enrollment and must agree to use a medically acceptable means of 
contraception from screening through at least 6 months after the last dose of 
investigational medicinal product (IMP).
Males: Subjects with female partners of child-bearing potential must agree to use
medically acceptable contraception after signing the ICF through at least 6 months after 
the last dose of IMP. Male subjects must also agree not to donate sperm during the study 
and for 6 months after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable:  
established use (for a period of at least 1 month) of oral, injected or implanted hormonal 
contraception; placement of an intrauterine device or intrauterine system; use of a double-
barrier method of contraception (condom or occlusive cap with use of a spermicide) or 
male sterilization.  
5. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study.
6. Subjects must be willing to adhere to study procedures.
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Subject compliance issues during participation in the RB-US-13-0003 study which, in the 
opinion of the Investigator, could potentially compromise subject safety.
2. Women of childbearing potential who have a positive pregnancy test at the RB-US-13-
0003 EOS Visit, who are pregnant or breastfeeding, seeking pregnancy, or failing to use 
adequate contraceptive methods during the study.
3. History of suicidal ideation within 28 days prior to signing the ICF as evidenced by 
answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the C-SSRS “since 


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last visit” assessment (completed in the EOS Visit for Study RB-US-13-0003); or history 
of a suicide attempt (per the C-SSRS “screening/baseline” assessment for the current 
study) in the 6 months prior to signing the ICF. 
4. Taking any cytochrome P450 3A4 and 2C8 inducers and inhibitors; self-reported 
additional buprenorphine (in addition to amount administered per protocol as part of 
subject’s participation in Study RB-US-13-0003); or OTC and/or herbal supplements 
with the potential to prolong QTc as per Section 6.10.1 within 28 days of Day 1; unless 
prior written approval is obtained from the Medical Monitor. 


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5
STUDY TREATMENTS
5.1
Description of Treatment
RBP-6000 contains buprenorphine in the ATRIGEL delivery system.  RBP-6000 is 
manufactured according to Good Manufacturing Practice standards.  RBP-6000 will be supplied 
as a single-syringe system, which is prefilled with RBP-6000.  The entire contents of the 
prefilled syringe will be administered.  (See Appendix 2: IMP Preparation and Dispensing 
Procedures for detailed dosage instructions).  
5.2
Treatments Administered
A single SC dose will be injected by an individual who is medically qualified to perform the 
procedure and delegated by the Principal Investigator to perform the task.  Injections of 
RBP-6000 will be administered in the abdominal area below the waist but above the hip bone; 
more specifically, injection should occur in the region where the body curves at the side to about 
2 inches from the middle of the abdomen with adequate amounts of subcutaneous tissue that 
does not have excessive pigment, nodules, lesions, or hair.  RBP-6000 will form a solid polymer 
depot that contains the buprenorphine.  As the depot degrades, buprenorphine will be released 
into the systemic circulation at a consistent rate over an approximately 28-day period.  For 
detailed instructions on use, see Appendix 2.
5.3
Selection and Timing of Dose for Each Subject
The study schedule is designed so that each of the injections will be separated by a minimum of 
26 days and a maximum of 35 days (28 days -2/+7 days) and will be given on alternate sides of 
the subject’s abdomen (see Appendix 2 and the Pharmacy Manual for detailed information on 
administration).  
If at an Injection Visit there is a safety concern with administration of RBP-6000, dosing can be 
delayed within the specified window. No injections are permitted outside of this window without 
prior consent from the Medical Monitor. 
Time of dose is defined as the time the RBP-6000 SC injection is complete.
5.4
Method of Assigning Subjects to Treatment Groups
There are no distinct treatment groups in this study. Doses of either 100 mg or 300 mg 
RBP-6000 may be administered to the subject, based on the medical judgment of the 
Investigator. The reason for dose change should be captured in the electronic case report form 
(eCRF)
Subjects will retain the subject number assigned to them in the RB-US-13-0003 study. The 
subject number will be recorded in the source document and eCRF.


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5.5
Blinding
Not applicable; this is an open-label study 
5.6
Restrictions
Subjects should be advised to avoid strenuous exercise. 
See section 6.10.1 for prohibited concomitant medications. 
5.7
Dosing Compliance
IMP will be administered by a designated and qualified licensed healthcare provider, unless a 
designated person is pre-approved by the Sponsor.  The time of dose and any dosing 
observations will be recorded in source documentation; in addition, time of dose will be recorded 
in the eCRF. Time of dose is defined as the time the RBP-6000 SC injection is complete.  The 
Investigator or designated individual will maintain a log of all IMPs dispensed and returned (if 
applicable).  The Investigator agrees not to supply RBP-6000 to any person except study 
personnel for SC injection of subjects in this study.  
5.8
Packaging and Labeling
RBP-6000 will be identified as an investigational compound and will be packaged and labeled in 
a manner consistent with the study design and applicable regulations.
5.9
Product Quality Complaints
Any issues noted (something out of the ordinary) with the packaging, labeling or RBP-6000 
product should be immediately reported.  Please refer to the Pharmacy Manual for detailed 
instructions.
5.10
Storage and Accountability
RBP-6000 should be stored under refrigerated conditions at 2ºC to 8ºC (36°F to 46°F).  
Temperature excursions in the range of 8°C to 25°C (46°F to 77°F) are permitted for a maximum 
duration of 48 hours; temperature excursions in the range of -20°C to 2°C (-4°F to 36°F) are 
permitted for a maximum duration of 7 days. Temperature excursions outside of this range 
should be reported to the Sponsor immediately and approval should be obtained before use, 
please refer to the pharmacy manual for details.
The Investigator or designee is responsible for ensuring that all IMP received at the site is 
inventoried and accounted for throughout the study. IMP must be handled strictly in accordance 
with the protocol, handling guidelines and the label, and must be stored in a locked, limited 
access area under appropriate environmental conditions. The Investigator must ensure that proper 
conditions exist for storage of study treatments. The dispensing of IMP to the subject must be 
documented.  Re-supply of RBP-6000 will be managed by IWRS and automatic shipments will 


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be processed based upon enrollment status and current available stock at the site (see Pharmacy 
Manual for further information on re-supply shipments).
Unused IMP must be available for verification by the site’s CRA during on-site monitoring 
visits. All used syringes components will be disposed of in accordance with the site’s standard 
operating procedure (SOP) or pharmacy destruction policy, which will be reviewed by the CRA 
before use. All used IMP packaging components should be retained for the verification by the 
CRA before disposal is permitted.
5.11
IMP Retention at Study Site
All unused RBP-6000 must be returned to the warehouse before the end of the study. The 
warehouse will arrange for the appropriate and timely destruction of all returned, unused 
RBP-6000. 


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6
STUDY PROCEDURES
The SOE for this study is provided in Appendix 1.
6.1
Medical History
A detailed medical history will be re-collected for this study up until signing the ICF. This will 
include information regarding the subject’s full history of medical and psychiatric conditions; 
diagnoses; procedures; concomitant medications; demographic information; use of tobacco, 
drugs of abuse, alcohol, and caffeine; and any other noteworthy medical information, including 
suicidality measured using the C-SSRS, hospitalizations and the reason for admission 
(medical/surgical/psychiatric/other). Any pre-planned surgeries or procedures outside of the 
scope of this study should also be considered as part of medical history. The medical history also 
should include medical events that occurred during a subject’s participation in Study RB-US-13-
0001 and/or RB-US-13-0003, and are deemed relevant in the opinion of the Principal 
Investigator. Any relevant updates to medical history information that the Investigator or 
medically-qualified designee becomes aware of during the course of the study should also be 
recorded.
Surgical procedures, planned before enrollment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion.  In this case the medical condition 
should be reported in the subject’s medical history.
6.2
Physical Examination
A physical examination will be performed by the Investigator or medically qualified designee at 
the EOS Visit for study RB-US-13-0003. Assessments for general appearance, chest/lungs, heart, 
abdomen and the brief neurological assessment will serve as the screening values for the present 
study. If any clinically significant abnormal findings were observed before the INDV-6000-301 
ICF was signed (including those noted during the RB-US-13-0003 EOS), these findings should 
be recorded on the Medical History case report form (eCRF). 
A brief physical exam will be repeated at EOS for INDV-6000-301. The physical examination 
will consist of an examination of the following:  general appearance, chest/lungs, heart, abdomen 
and a brief neurological assessment.  The examination will not include a pelvic, breast, or rectal 
examination.  If any clinically significant change from screening is noted, it will be reported as 
an AE and followed up to resolution or until reaching a stable end point.
6.3
Body Mass Index and Hip-to-Waist Ratio
A subject’s weight (kg) (in ordinary indoor clothing with shoes off) will be measured at the EOS 
Visit for Study RB-US-13-0003. A subject’s height (cm) will be re-measured at the INDV-6000-
301 Screening Visit.  These measurements (weight and height) will be inputted into the eCRF in 
order to calculate a BMI (i.e., BMI calculation will be done automatically in the electronic data 
capture system).  BMI is defined as the subject’s weight in kg divided by the square of the 
subject’s height in meters (kg/m2).  (Note: Calculation of BMI in the EOS Visit for Study RB-


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US-13-0003 will use the height measurement originally taken at screening for the prior study.)  
A subject’s amount of abdominal fat (waist-to-hip ratio) will be determined using measurement 
of both waist and hip circumference (cm) at the EOS Visit for Study RB-US-13-0003; this 
previously calculated waist-to-hip ratio will be recorded in the eCRF.  These values will serve as 
the screening values for this study. The above assessments will be repeated at the EOS/ET Visit 
for INDV-6000-301, as detailed in the SOE (Appendix 1).
6.4
Vital Signs
Evaluation of vital signs will be performed after the subject has been supine for ≥ 3 minutes and 
will include a measurement of systolic and diastolic blood pressure, pulse rate, pulse oximetry, 
respiratory rate, and oral temperature.  
If clinically significant findings, as determined by the Investigator or medically qualified Sub-
investigator, occur in any vital sign measurement, that measurement will be captured as an AE 
and repeated at medically appropriate intervals until the value returns to an acceptable range, a 
specific diagnosis is established, or the condition is otherwise explained.
Assessments will be recorded in the source documents and eCRF and will be performed at the 
time points detailed in the SOE (Appendix 1).
6.5
Clinical Laboratory Tests
6.5.1
Laboratory Parameters
All clinical laboratory assessments will be performed by a clinical laboratory accredited by the 
College of American Pathologists or with a Certificate of Compliance or Accreditation (or 
Certificate of Waiver for CLIA-waived tests) issued by the Center for Medicare & Medicaid 
Services. The laboratory assessments will include routine and screening laboratory tests. 
See the SOE in Appendix 1 for the timing of the specific required laboratory tests which are 
listed in Table 2. 
Any abnormal hematology, chemistry, or urinalysis test result deemed clinically significant by 
the Investigator will be repeated.  For any test abnormality deemed clinically significant, an AE 
will be recorded (unless the result was considered erroneous) and repeat analysis will be 
performed until resolution or until the Investigator determines that resolution of the laboratory 
abnormality is not expected.  
Subjects will be in a seated or supine position during blood collection.  Clinical laboratory panels 
are listed in Table 2.


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Table 2
List of Laboratory Tests
Hematology:
Hematocrit
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelet count
Red blood cell count
White blood cell count with differential
Urinalysis:
Appearance
Bilirubin
Color
Glucose
Ketones
Leucocyte esterase
Microscopic examination of sedimenta
Nitrite
Occult blood
pH
Protein
Specific gravity
Urobilinogen
Pregnancy:
Urine Pregnancy (only for females not postmenopausal or 
surgically sterile for at least 1 year)
Urine Drug Screen:
Opioidsb
Cocaine
Amphetamines
Methadone
Cannabinoids
Barbiturates
Benzodiazepines
Methamphetamine
Phencyclidine
Serum Chemistry:
Albumin
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Amylase
Aspartate aminotransferase (AST)
Blood urea nitrogen
Calcium
Calculated creatinine clearancec
Carbon dioxide
Chloride
Creatinine
Creatine kinase and subtypes
Gamma-glutamyl transferase
Globulin
Glucose (non-fasting)
High-density lipoprotein (HDL)
Lactate dehydrogenase
Lipase
Low-density lipoprotein (LDL)
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin
Total cholesterol
Total protein
Triglycerides
Uric acid
a
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to WBC count, RBC count, casts, and crystals).
b
Oxycodone may not show up in all opiate assays and should be assessed separately.
c
Creatinine clearance will be calculated according to the Cockcroft-Gault equation.
6.5.2
Sample Collection, Storage, and Shipping
All blood sampling will be by individual venipuncture or with the use of a saline lock.  Blood 
and urine sample collection and processing procedures will be outlined in a separate reference 
manual to be provided to the site.


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6.5.3
Reference Ranges
Up-to-date reference ranges for the above investigations must be obtained from the laboratory 
performing analyses prior to the start of the study and be updated as appropriate during the 
course of the study.
6.5.4
Laboratory Results Review
The Investigator will review the results and comment on the laboratory results sheet for all 
abnormal values, identifying those that are abnormal but not clinically significant as well as 
those that are significantly abnormal.  The Investigator will sign and date the laboratory results 
sheet to indicate that the review has taken place.
Clinical Laboratory Changes:  It is the Investigator’s responsibility to review the results of all 
laboratory tests as they become available.  This review will be documented by the Investigator 
on the laboratory report.  For each abnormal laboratory test result, the Investigator needs to 
ascertain if this is a clinically significant abnormal change from baseline for that individual 
subject. 
Any liver abnormality > 3 x ULN should be carefully assessed by the Investigator to determine 
whether it should be considered an AE. Guidance for the procedures to follow for elevated liver 
function tests are provided in Appendix 8.
6.6
Suicidality Assessments  
The C-SSRS is a questionnaire designed for assessment of suicidal ideation and behavior in 
adolescents and adults (Posner 2011).  Suicidality assessment will be conducted according to the 
SOE table in Appendix 1, using two versions of the C-SSRS (“baseline/screening” and “since 
last visit”). The C-SSRS “baseline/screening” assessment will include both a lifetime and past 6-
month time interval.  The two C-SSRS versions are presented in Appendix 4 and Appendix 5. 
If a subject becomes suicidal during the study, the Investigator should provide appropriate 
treatment to the subject.  If the suicidality is deemed to be related to IMP and it is within 14 days 
of an injection, the depot may be removed (Section 6.12.1).
If there is a positive (“yes”) response on the C-SSRS (“since last visit”) assessment after 
screening, the subject will be evaluated by the Investigator for continuation in the study.  If 
needed, the Investigator can consult with the Medical Monitor.
6.7
Local Injection Site Tolerability
6.7.1
Injection Site Evaluation
At Injection Visits 2 through the EOS/ET Visit, the local injection site will be evaluated for 
potential reaction and evidence of any attempts to remove the depot medication following a 
previous injection of RBP-6000.  This evaluation should be performed by the Investigator or a 
trained and qualified licensed healthcare professional.  Any detected removal attempts should be 


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discussed with the Medical Monitor to determine whether the subject should be terminated from 
the study.  In addition, detection of any depot removal attempt at the EOS Visit for the prior 
study (Study RB-US-13-0003) should be discussed with the Medical Monitor to determine 
whether a subject should be enrolled into the current study.  
Depot removal attempts are to be captured in the e-CRF (using “Yes” or “No” answers). 
6.7.2
Injection Site Grading
Local injection site grading will be performed by the Investigator or a trained and qualified 
licensed healthcare professional, unless a designated person is pre-approved by the Sponsor, 
according to the SOE in Appendix 1.  Grading should be performed 1 hour (+ 30 minutes) post-
completion of injection.  Injection sites will be assessed for pain, tenderness, erythema/redness, 
induration, or swelling.  Local injection site tolerability will be assigned a severity grade, 
including none (grade 0), mild (grade 1), moderate (grade 2), severe (grade 3), or potentially life 
threatening (grade 4) utilizing the 5-point Injection Site Grading Scale in Appendix 6.
6.7.3
Injection Site Pain Visual Analog Scale (VAS) 
Injection site pain will be assessed by the subject at each Injection Visit with a 100 mm VAS 
scale ranging from 0 to 100, where 0 represents “no pain” and 100 represents “maximum pain”
(Appendix 7). The injection site pain VAS scores will be obtained approximately 1 hour after 
each injection. The timing of the injection site pain VAS assessment should be measured starting 
from the end of the injection. In addition to self-rating pain level by marking on the line the point 
they feel best represents their perception of their current state, the subject will also answer the 
following question with either a “Yes” or “No”: Are you currently experiencing any burning or 
stinging at the injection site?
Copies of any pre-printed VAS paper forms to be used by subjects for self-assessment of their 
injection site pain must be checked to confirm that the VAS rating scale measures exactly 100 
mm (3.94 in) in length.
6.8
Pharmacokinetic Assessments
Not Applicable
6.9
Adverse Events Assessments
6.9.1
Adverse Event Definition
In accordance with ICH and United States Food and Drug Administration (FDA) guidance, any 
untoward medical occurrence incurred by a subject that occurs after the first study-related 
procedure to the completion of the Safety Follow-Up Visit and is associated with the use of the 
drug, regardless of the presence of causal relationship, is a reportable AE.  AEs that are ongoing 
at the time of the RB-US-13-0003 EOS visit will be recorded in the eCRF for this study. 


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All subjects participating in the study that have a EOS/ET Visit will be contacted by telephone 
for a safety follow-up assessment of AEs (new or ongoing) and use of any concomitant 
medications. 
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered AEs if they:

Result in discontinuation from the study,

Require treatment or any other therapeutic intervention,

Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality), or

Are associated with clinical signs or symptoms that would have a significant clinical 
impact, as determined by the Investigator.
6.9.2
Treatment-Emergent Adverse Event Definition
A TEAE is an AE that either commenced following initiation of IMP or was present prior to the 
initiation of IMP, but increased in frequency or severity following initiation of treatment, 
regardless of causality.
6.9.3
Performing Adverse Events Assessments
The Investigator is ultimately responsible for assessing and reporting all AEs as outlined in the 
protocol.  The assessment of AEs may be delegated to a medically qualified Sub-investigator, 
trained on this study protocol, who is listed on the FDA Form 1572 or equivalent document, and 
on the delegation of authority form.
AEs should be volunteered by the subject or solicited from the subject using a standard 
statement, obtained from examination of the subject at a site visit, or from observations of 
clinically significant laboratory values or special examination abnormal values.  If an event 
assessed by one of the study scales requires intervention, or if in the opinion of the Investigator, 
it is clinically significant, then it will be reported as an AE. Any ongoing AEs reported in the 
RB-US-13-0003 study will be recorded in the eCRF for this study. 
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 drug-related or not.
6.9.4
Timing
AEs will be captured from the time the subject gives informed consent until the subject 
completes the Safety Follow-Up Visit.   


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Surgical procedures, planned before enrollment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion.  In this case the medical condition 
should be reported in the subject’s medical history (see Section 6.1).  
6.9.5
Severity
Adverse events with changes in severity should be documented as separate events.
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; hospitalization is probable.  
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as “serious,” which is based on 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.
6.9.6
Relationship
The Investigator or a medically qualified Sub-investigator, trained on this study protocol, listed 
on the 1572 form or equivalent document and on the delegation of authority form is responsible 
for determining the AE relationship to the IMP.
The following categories will be used to define the relationship of an AE to the administration of 
the IMP:
Not Related:
Data are available to identify a clear alternative cause for the AE other than 
the IMP.
Related:
The cause of the AE is related to the investigational product and cannot be 
reasonably explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy, and/or other interventions).
6.9.7
Expectedness
An unexpected AE is any AE, the nature and severity of which is not consistent with the IB for 
the IMP.


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6.9.8
Clinical Significance
The Investigator or medically qualified Sub-investigator, trained on this study protocol, listed on 
the 1572 form and on the delegation of authority form is responsible for determining clinical 
significance of abnormal assessment results (e.g., laboratory results) for the subject.
6.9.9
Clinical Laboratory Adverse Events
Changes in laboratory values or vital signs, or other safety parameters (e.g., neurological and 
clinical symptom assessments) as noted in the protocol are a subset of AEs and are reportable 
only if considered to be clinically significant by the Investigator or medically qualified Sub-
investigator except that:
•
Baseline assessments are differentiated from AE/symptoms that are incurred post 
informed consent.  These baseline lab assessments, if determined to be clinically 
significant abnormal values, reflect the status of the subject prior to study participation.  
These clinically significant pre-dose abnormal assessments without clinical symptoms 
will not be reported as AEs. 
It is noted that any liver abnormality > 3 x ULN should be carefully assessed by the Investigator 
to determine whether it should be considered an AE. Guidance for the procedures to follow for 
elevated liver function tests are provided in Appendix 8.
6.9.10
Serious Adverse Events
6.9.11
Serious Adverse Event Definition
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 

death, 

life-threatening AE,

hospitalization or prolongation of existing hospitalization, 

a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or

a congenital anomaly or birth defect.
“Important medical events may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.” 
6.9.11.1
Suspected Unexpected Serious Adverse Event Definition
A suspected unexpected serious adverse reaction (SUSAR) is any SAE that, in its nature or 
severity, is inconsistent with available medication information (e.g., IB or Package Insert). 
Indivior Pharmacovigilance will determine if an SAE is a SUSAR.


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6.9.11.2
Reporting Serious Adverse Events
All SAEs will be reported to the Sponsor by the Investigator or designee by email or fax within 
24 hours of discovery, using the form provided by the Sponsor.  The SAE report should also be 
emailed to the Medical Monitor.
In the event of an SAE, the Investigator or designee will notify Indivior Pharmacovigilance:
Email: PatientSafetyNA@indivior.com
Fax: (804) 423-8951
Indivior Inc.
10710 Midlothian Turnpike, Suite 430
Richmond, VA 23235
In the event that medical discussion is required for an SAE, the Medical Monitor should be 
contacted:
24-hour number: 
Email: 
In the event of an emergency, a back-up has also been identified: 
 
Email: 
The Investigator or designee must inform the institutional review board (IRB) immediately 
regarding any AE (does not have to be causally related) that is both serious and unexpected 
(SUSAR); or that represents a series of AEs that on analysis is unanticipated, or occurs at an 
unanticipated frequency, or otherwise represents an unanticipated safety risk to the study subject. 
The IRB may subsequently choose to modify the informed consent or request changes to the 
protocol or IB.  
Subjects with ongoing SAEs at the Safety Follow-Up Visit that in the opinion of the Investigator 
or medically qualified Sub-investigator are associated with the study, will be followed and 
reported as described in Section 6.9.11.2.
6.9.12
Pregnancy
If a pregnancy is confirmed at any time during the study through a urine pregnancy test
performed by the study laboratory, the subject will be discontinued from the study and will 
undergo all final study visit procedures (with the exception of a urine pregnancy test). If the 
partner of a study subject becomes pregnant, the pregnancy will be reported to the clinical unit 
within 48 hours of the subject’s knowledge of the pregnancy. The Investigator will attempt to 
collect pregnancy information on any female partner of a male study subject who becomes 
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from the female partner directly, the Investigator will record pregnancy information on the 
appropriate form and submit it to Indivior or designated representative within 24 hours of 
learning of the partner’s pregnancy. 
All confirmed pregnancies that occur within this study will be followed until resolution (i.e., 
termination [voluntary or spontaneous] or birth).  
Pregnancy ([study subject or the partner of a study subject] [without associated unexpected or 
adverse sequelae]) is not a reportable AE but must be reported to the Sponsor within 24 hours of 
the Investigator or study staff first being aware of the subject’s condition. 
6.10
Concomitant Medication Assessments
The Investigator or designee will record any concomitant therapies given during the course of the 
study on the concomitant medication page of the subject’s source documentation and eCRF. Any 
changes in concomitant therapy during the study will also be documented, including cessation of 
therapy, initiation of therapy, and dose changes.
Concomitant therapies are defined as prescribed medications and over the counter (OTC) 
preparations, including herbal preparations and vitamins, other than study medication and 
supplementary medication that the subject receives within 28 days of screening and for the 
during the course of the study.  Any medication taken by the subject is to be reported by the 
subject and noted on the subject’s source document and concomitant medication page.  Any 
changes in concomitant therapy during the study will be documented, including cessation of 
therapy, initiation of therapy, and dose changes.
Subjects who are medically prescribed benzodiazepines will be evaluated on a case-by-case basis 
for inclusion in the INDV-6000-301 study.  The Investigator will discuss these subjects with the 
Medical Monitor before enrolling into the INDV-6000-301 study.
The Investigator or designee will also record any medications given for the treatment of AEs on 
the concomitant medication page.  
6.10.1
Prohibited Concomitant Medications
The sponsor must approve any prohibited concomitant medications before administration except 
in cases of immediate medical need. In cases of immediate medical need, consult the Medical 
Monitor as soon as possible following administration of a prohibited medication for any further 
questions and to ensure appropriate documentation. All concomitant medications should be 
recorded in the eCRF. 
The following medications are prohibited: 

All cytochrome P450 3A4 and 2C8 inducers and inhibitors inclusive of, but not limited to 
those in Appendix 3

Buprenorphine (in addition to RBP-6000 treatment)

OTC and/or herbal supplements with the potential to prolong QTc. (For example: 
famotidine (e.g., Pepcid brand), ephedrine, and some Chinese herbal supplements.)


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The use of all opioids should be avoided in this study.

If the subject self-medicates with these medications, document reason for use 
appropriately.

Any prescribed opioids for other uses (such as pain) should be discussed with the 
Medical Monitor.
The use of the following medications requires careful consideration, and should be discussed 
with the Medical Monitor. If treatment is necessary, careful monitoring is required for: 

prescription medications known to prolong the QTc interval

general anesthetics, benzodiazepines, phenothiazines, other tranquilizers, and 
sedative/hypnotics.
6.11
Counseling/Behavioral Therapy
After enrollment, subjects will receive manual-guided, individual behavioral therapy according 
to the SOE indicated in Appendix 1 . Behavioral therapy can be conducted by any appropriately 
trained staff member at the site. A reference manual will be provided to each site by the Sponsor.
6.12
Removal of Subjects from the Study
Subjects will be free to withdraw at any time for any reason, or they may be withdrawn if 
necessary, to protect their health and safety or the integrity of the study data.  
The Investigator or medically qualified Sub-investigator may choose to withdraw a subject from 
the study at any time.  Reasons for removing a subject from the study may include, but are not 
limited to the following:
•
Protocol deviation that comprises or may compromise data integrity, protocol compliance, or 
subject safety;
•
AE that compromises or may compromise subject safety;

Sponsor or Investigator terminates the study;

Subject requests to be discontinued from the study (i.e., subject declines further study 
participation); or

Subject becomes pregnant.
If a subject withdraws prematurely from the study after receiving IMP, the primary reason for 
withdrawal will be documented as 1 of the above, lost to follow-up, or other in the source 
documentation. 
6.12.1
Early Removal of RBP-6000
In the event of an emergency, toxicity is suspected, or if a subject withdraws or is withdrawn 
within the first 14 days of receiving an injection of RBP-6000, subjects may have the option to 
have the depot surgically removed by a physician delegated to perform surgery. The medically 
responsible physician should carefully discuss this option with subjects and the feasibility of 


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extracting the depot. The surgical procedure requires a small incision in the abdomen where the 
depot was placed, removal of the depot with forceps, and suturing to close the incision. The 
subject should have the ET assessments performed at the time of early removal of RBP-6000 and 
a safety follow up call 28 days later, as per the SOE (Appendix 1). 
The extracted RBP-6000 depot will be disposed as per the SOPs at the clinical site.  
Detailed RBP-6000 depot removal instructions are in Appendix 2.
6.12.2
Stopping Rules
The Investigator must contact the Sponsor immediately to discuss whether to suspend dosing if 
an AE or laboratory abnormalities indicates that continued dosing of subsequent subjects would 
not be tolerated or would jeopardize the subjects’ safety.  The Sponsor alone may suspend dosing 
at any time for any reason.
Factors that must be considered for suspension of dosing include the frequency, severity, clinical 
significance, possible causality, and anticipated reversibility of all observed AEs or laboratory 
abnormalities for each specific SC injection group.  If dosing is suspended, the IRB will be 
notified in accordance with IRB requirements.
Guidance for the procedures to follow for elevated liver function tests are provided in Appendix 
8.
6.12.3
Lost to Follow-up
A subject is considered as lost to follow-up if the site has made reasonable attempts to contact 
the subject and received no response. This may be due to the subject not returning to the site, or 
not answering the safety follow-up telephone call. A minimum of 2 documented telephone calls 
followed by a certified mailed letter is considered reasonable. At that point, the subject may be 
considered lost to follow-up and any open AEs may be closed. 
6.12.4
Screen Failures
A screen failure subject is a subject that signed the ICF but did not receive IMP.
6.13
Other Study Procedures
6.13.1
Unscheduled Visits
If unscheduled visits occur, the Investigator must record the following in the subject’s source 
documentation:

Any AEs

Reason for unscheduled visit

Recording of any changes or additions to concomitant medications dose or regimen

Any clinical assessments deemed appropriate for the clinical care of the subject


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Unscheduled visits should not alter the timing of the routine study schedule.
6.14
Appropriateness of Measurements
All measurements to be obtained in this study are standard and widely used.


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7
STUDY ACTIVITIES
This study will be conducted as a fully non-residential (outpatient) study.  An overview of the 
study is shown in Figure 1.  Details on procedures/activities for this study are provided in 
Section 6 and SOE is provided in Appendix 1.


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8
QUALITY CONTROL AND ASSURANCE
8.1
Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the Investigators 
and associated personnel before the study, periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the Sponsor’s (or 
designee’s) database.  Written instructions will be provided for IMP preparation and dosing, 
collection, preparation, and shipment of blood, plasma, and urine samples.  Guidelines for eCRF 
completion will be provided and reviewed with study personnel before the start of the study.  
The Sponsor (or designee) will review eCRFs for accuracy and completeness during on-site 
monitoring visits and after transmission to the Sponsor (or designee).  Any discrepancies will be 
resolved with the Investigator or suitably qualified designee, as appropriate.
8.2
Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines.  
In accordance with the standards defined in Sponsor SOPs and applicable regulatory 
requirements, clinical studies sponsored by Sponsor are subject to Sponsor Quality Audits at the 
study sites that will be conducted by personnel from an appropriate unit. Site audits may be 
performed by the Sponsor’s (or contractor’s) qualified Quality Assurance (QA) team, which is an 
independent function from the study conduct team. QA audits may include review of, but are not 
limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents. The Investigator agrees to participate with QA 
audits conducted at a reasonable time in a reasonable manner. Full consultation with the 
Investigator will be made prior to and during such a QA audit, which will be conducted 
according to the Sponsor's (or contractor's) QA SOPs. In addition, this study may be 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 the Sponsor immediately if this occurs and must fully cooperate with 
the inspection conducted at a reasonable time in a reasonable manner.


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9
PLANNED STATISTICAL METHODS
9.1
General Considerations
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 the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays.
This section describes the method for the analysis population and planned analyses.  Additional 
unplanned analyses may be required after all planned analyses have been completed.  Any 
unplanned analyses will be clearly identified in the clinical study report.  Any deviations from 
the analyses described below will be included in the SAP, which will form Appendix 16.1.9 of 
the clinical study report.
Continuous variables will be summarized using descriptive statistics such as means, standard 
deviations (SD), medians, minimums, and maximums.  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 end of study for all subjects 
enrolled.  
9.2
Determination of Sample Size
All subjects who completed the RB-US-13-0003 study may be eligible to enroll into this study. 
This will be approximately 300 subjects.
9.3
Analysis Populations
The population used for all safety analyses will be comprised of all subjects who received at least 
1 dose of RBP-6000 in this study.
A completer is defined as a subject who completes the EOS visit (WK 25, Day 169). 
9.4
Demographics and Baseline Characteristics
Demographic and baseline characteristics (gender, race, age, weight, height) will be summarized 
using descriptive statistics. Qualitative variables (gender, race) will be summarized using 
frequencies while quantitative variables (age, weight, height) will be summarized using mean, 
SD, median, minimum, and maximum.
9.5
Primary Analysis
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the C-SSRS, concomitant 
medications; clinical laboratory results (hematology, chemistry and urinalysis); vital sign 


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measurements; physical examination results; body weight, height, BMI, and abdominal fat 
measurement (waist-to-hip ratio). Safety variables will be assessed with regards to the safety 
population. 
Baseline is defined as the value collected at Screening.  No imputation of missing values will be 
performed.
9.5.1.1
Adverse Events
All AEs will be coded using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and reported to the FDA. AEs that began after the EOS visit 
will not be included in the safety analysis. Only TEAEs occurring post administration of 
RBP-6000 will be included in the safety analysis (See Section 6.9.2).
The incidence of AEs (number and percent of subjects reporting the AE at least once during the 
study) will be summarized for all AEs, by the relationship to IMP and by severity.
9.5.1.2
Laboratory Data
Clinical laboratory assessments are conducted at screening and at the EOS visit, summary 
statistics for the absolute laboratory value and the change from baseline will be presented.  
9.5.1.3
Vital Signs
Vital signs measurements will be assessed for clinical relevance.  
9.5.1.4
Other Variables Related to Safety
Medical history will be coded using MedDRA and summarized by treatment group as described 
for AEs (Section 9.5.1.1).  Body weight, height, BMI, and abdominal fat measurement (waist-to-
hip ratio) will be summarized using descriptive statistics (mean, median, SD, minimum, 
maximum), including change from baseline.
Total C-SSRS scores will be summarized using descriptive statistics (mean, median, SD, 
minimum, maximum), including change from baseline.  
Prior and concomitant medications will be coded using the most recent version of the World 
Health Organization (WHO) Drug dictionary.  Incidence (number and percent of subjects 
reporting the medication at least once during the study) will be summarized for all concomitant 
medications.
Local injection site tolerability as assessed by the Injection Site Grading scale will be 
summarized by category and severity using frequency counts and percentages similar to 
summaries for AEs (Section 9.5.1.1).  Injection Site Pain VAS scores will be summarized by 
dose and injection.  The burning/stinging categorical variable (Yes/No) will be summarized by 
percent of responses for each dose.


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9.6
Handling of Missing Data
Missing data will not be imputed.  
9.7
Subjects Who Withdraw from the Study
Subjects who withdraw after receiving RBP-6000 will not be replaced.
9.8
Interim Analyses
If an interim analysis were to be performed for this study the details will be outlined in the 
statistical analysis plan. 


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10 ADMINISTRATIVE CONSIDERATIONS
10.1
Investigators and Study Administrative Structure
10.1.1
Sponsor
Indivior Inc.
10710 Midlothian Turnpike, Suite 430
Richmond, VA 23235
10.1.2
Investigational Site(s)
This study will be conducted at up to 31 sites in the US.
10.1.3
Laboratories
Laboratories used for the safety laboratory tests (serum chemistry, hematology, serology, and 
urinalysis), will be conducted at a central laboratory that is certified and accredited to perform 
the assigned assessments.
10.2
Institutional Review Board Approval
The protocol will be reviewed by an independent, appropriately constituted, centralized IRB. 
Study enrolment and protocol related procedures, which do not form part of the subject’s normal 
clinical treatment, will not be performed until the IRB of record has provided written approval of 
the protocol or a modification thereof.  The IRB must be constituted and operate in accordance 
with the principles and requirements of ICH GCP.
IMP can only be supplied to the Investigator after documentation on all ethical and legal 
requirements for starting the study has been received by the Sponsor.  This documentation must 
also include an IRB membership list that contains member’s occupations.  If the IRB will not 
disclose the names of the committee members, the IRB Number may be accepted as a substitute 
for this list.  Formal approval by the IRB should mention the study title, study code, study site 
(or region or area of jurisdiction, as applicable), and any other documents reviewed.  It must 
mention the date on which the decision was made and must be officially signed by a committee 
member.
10.3
Ethical Conduct of the Study
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH GCP guidelines, and applicable regulatory and country-specific 
requirements.  GCP is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects.  
Compliance with this standard provides the public assurance that the rights, safety, and 
well-being of study subjects are protected and that the clinical study data are credible.


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10.4
Subject Informed Consent
Prior to entering the study, the Investigator or designated individual must explain to each subject 
the nature of the study, its purpose, procedures, expected duration, alternative therapies 
available, and the benefits and risks involved in study participation. Subjects must be given the 
IRB-approved ICF to review and the opportunity to ask questions. In the case of a non-medically 
qualified person conducting the consent process, he/she must have ready access to an 
investigator to whom any questions from the study subject may be referred. Subjects must be 
informed of their right to withdraw from the study at any time without prejudice. The potential 
subjects should be able to answer simple questions about the study after the ICF has been 
reviewed and explained. After this explanation and before any study-specific procedures have 
been performed, the subject must voluntarily sign and date the ICF to indicate the desire to 
participate in the study. The Investigator or the individual designated to conduct the consent 
discussion for the Investigator must also sign and date the ICF and the time (hour and minute) 
the consent is signed must be recorded. Verbal informed consent followed by a signed consent 
short form is not acceptable to Sponsor. Prior to participation in the study, the subject must 
receive a copy of the signed and dated ICF along with an emergency card with contact 
information for the Investigator and site staff in the event of a medical emergency during the 
study.
10.5
Subject Confidentiality
All subject-identifying documentation generated in this study must be considered confidential 
and must not be disclosed to any persons not directly concerned with the study without written 
permission from the subject.  However, authorized regulatory officials and Sponsor 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 the Sponsor.
Each subject will be identified by initials and an assigned subject number when reporting study 
information to any entity outside of the study center. Data containing subject identification must 
not be removed from the site without subject identifiers having been redacted.
10.6
Study Monitoring
In accordance with applicable regulations, GCP, and Sponsor procedures, the CRA 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 CRA 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 must make available for direct access all study-related records upon 
request of the Sponsor, the Sponsor’s agents, CRA, auditors, and/or IRB. The Sponsor’s CRAs 
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 


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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.
10.6.1
Study and Site Closure
Upon completion of the study, study closeout activities must be conducted by the Sponsor or its 
designee in conjunction with the Investigator, as appropriate.
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason.  If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reason[s] for taking such action) at that time.  The Sponsor will 
also inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  If required by applicable regulations, the Investigator must inform the 
IRB promptly and provide the reason(s) for the suspension or termination.  If the study is 
prematurely discontinued, all study data and IMP remaining on site must be returned to the 
Sponsor or its designee.
10.7
Case Report Forms and Study Records
The Investigator is responsible for the quality of the data recorded in the eCRFs.  The data 
recorded should be a complete and accurate account of the subject’s record collected during the 
study.  Study data are not to be gathered directly onto the eCRF but must be gathered onto 
primary source documents at the clinical site. Completion of source documents will precede the 
completion of the eCRF.  Source documents may be electronic, hard copy, or a combination of 
both.  Source documents 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 investigators and made available for 
direct inspection by the authorized study personnel outlined in the ICF. Site staff will receive 
training on the eCRF completion guidelines and requirements for source documentation which 
will provided by Sponsor or its designee.  
Completed eCRFs will be reviewed by the CRA in line with eCRF completion guidelines for the 
study to ensure completeness and consistency.  The clinical monitoring plan for this study will 
define the level of source data verification required.  Any discrepancies found during the eCRF 
review will be clarified by the Investigator or designated individual.  This includes eCRF 
reviews at the site by Sponsor or its designee, or during quality assurance review of the data.  
An explanation must be documented for any missing data.  Any changes to information in the 
study progress notes and other source documents will be initialed and dated on the day the 
change is made by a site staff member authorized to make the change.  Changes will be made by 
striking a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (e.g., wrong data right data).  If the reason for the change is not 


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apparent, a brief explanation for the change will be written in the source documentation by the 
site.
The Investigator must sign and date a declaration attesting to his/her responsibility for the quality 
of all data recorded, and that the data represents a complete and accurate record of each subject’s 
participation in the study.  
All eCRF entries, corrections, and alterations must be made by the Investigator or designated 
individual.  The Investigator or designated individual must adjust the eCRF (if applicable) and 
complete the query.
10.8
Data Monitoring Committee
Not applicable; there will be no data monitoring committee for this study.
10.9
Protocol Deviations
This study is intended to be conducted as described in this protocol. At the outset of the study, a 
process for defining and handling protocol deviations will be established. This will include 
determining which deviations will be designated “important” and require immediate notification 
to the Sponsor. In the event of a deviation from the protocol due to an emergency, accident, or 
mistake, the Investigator or designated individual must contact the Sponsor at the earliest 
possible time by telephone. This will allow an early joint decision regarding the subject’s 
continuation in the study. This decision will be documented by the Investigator and the Sponsor, 
and reviewed by the CRA. All deviations from the protocol must be documented. The 
Investigator or designated individual will be responsible for identifying and reporting all 
deviations, which are defined as isolated occurrences involving a procedure that did not follow 
the study protocol or study-specific procedure. Deviations will be reported as required to the IRB 
and in the final study report.
10.10 Access to Source Documentation
The Investigator must agree to complete a subject identification and enrolment log to permit easy 
identification of each subject during and after the study.  This document will be reviewed by the 
CRA for completeness.  The subject identification and enrollment log will be treated as 
confidential and will be filed by the Investigator in the study center file.  To ensure subject 
confidentiality, no copy will be made.  All reports and communications relating to the study will 
identify subjects by initials and assigned number only.  The Investigator must also complete a 
subject-screening log, which reports on all subjects who were seen to determine eligibility for 
inclusion in the study.
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all AEs; concomitant medications; IMP administered; date 
of study completion or early discontinuation, and reason for early discontinuation if applicable.


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10.11 Data Generation and Analysis
10.11.1 Data Collection and Data Management
Study specific data that has been outlined in the protocol will be entered into the clinical 
database by individual(s) designated by the Investigator in accordance with the eCRF 
Completion Guidelines.  Data is verified electronically using a series of on-line programmed edit 
checks that have been created by the Clinical Data Manager and programmed by the Clinical 
Data Programmer or Designee.  Data discrepancies will be brought to the attention of the clinical 
team and investigated by the CRA and Site Study Coordinator.  CRAs will review and verify all 
data collected in the eCRF against source documentation as defined in the clinical monitoring 
plan.  The CRA will work closely with the Site Study Coordinator to address any discrepancies 
which have been found so that proper resolutions can be made and documented into the clinical 
database.  An audit trail within the system will track all changes made to the data.
10.11.2 Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be generated and addressed by the investigational site.  Only 
authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail.  
10.12 Retention of Data
All documents pertaining to the study, including all versions of the approved study protocol, 
copy of the ICF document and Health Insurance Portability and Accountability Act documents, 
completed eCRFs, source documents (subject records, subject diaries, hospital records, 
laboratory records, drug accountability records, etc.), and other study-related documents will be 
retained in the permanent archives of the study site.
The Investigator must therefore notify and obtain approval in writing from the Sponsor prior to 
destruction of any study records or provide an opportunity for the Sponsor to collect such 
records.  If the investigator withdraws from the study (e.g., relocation, retirement) all study-
related records should be transferred, in a written agreement with the Sponsor, to a mutually 
agreed upon designee within a Sponsor-specified timeframe.
10.13 Financial Disclosure
The Sponsor requires, for each study, the disclosure of any financial interests from each 
investigator or sub-investigator, including financial interests of the spouse and each dependent 
child of the investigator who is directly involved in the treatment or evaluation of research 
subjects that could affect the reliability of data submitted to regulatory authorities. The collection 
of this financial interest information at the start of the study, as well as any updates should this 
information change, is required by the FDA when submitting a marketing application and is in 
line with the GCP requirement to consider any potential conflicts of interest.


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10.14 Publication and Disclosure Policy
A clinical study report will be prepared following completion of the study.  The report will be a 
record of the total study conduct and will be subject to Sponsor approval and restrictions on 
distribution/disclosure.
The study data will be owned by the Sponsor.  Publication of any and all data will be at the 
discretion of the Sponsor.  The Investigator will not disseminate, present, or publish any of the 
study data without the prior written approval of the Sponsor to do so.


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11 REFERENCE LIST
American Psychiatric Association (2013).  Diagnostic and Statistical Manual of Mental 
Disorders (5th edition).
Department of Justice, Economic Impact of Illicit Drug Use in American Society, 2011.
Drug Interaction Information: http://medicine.iupui.edu/clinpharm/ddis/clinical-table/. Accessed 
30 September 2016.
Indivior RBP-6000 Investigator's Brochure, Edition 5. 18 May 2016.
Nasser AF, Heidbreder C, Gomeni R, et al (2014).  A population pharmacokinetic and 
pharmacodynamic modelling approach to support the clinical development of RBP-6000, a new, 
subcutaneously injectable, long-acting, sustained-release formulation of buprenorphine, for the 
treatment of opioid dependence. Clin Pharmacokinet. DOI 10.1007/s40262-014-0155-0
Posner K, Brown GK, Stanley B, et al (2011).  The Columbia-suicide severity rating scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 168 (12): 1266-77.
RB-US-10-0011, Reckitt Benckiser Pharmaceuticals Internal report (2011). A Single-Dose, 
Open-Label Study of Depot Buprenorphine (RBP-6000) in Opioid-Dependent Individuals.
RB-US-11-0020, Reckitt Benckiser Pharmaceuticals Internal report (2013). A Multicenter, 
Open-Label, Single Ascending-Dose Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Depot Buprenorphine (RBP-6000) in Opioid-Dependent Subjects.
RB-US-12-0005, Reckitt Benckiser Pharmaceuticals Internal report (2015), An Open-Label, 
Multicenter, Multiple Dose Study of the Safety, Tolerability, Pharmacokinetics, Efficacy 
Markers, and Opioid Receptor Availability of Subcutaneous Injections of Depot Buprenorphine 
(RBP-6000) in Treatment Seeking Opioid-Dependent Subjects 
RB-US-13-0002, Reckitt Benckiser Pharmaceuticals Internal report (2015), A Multiple-Dose 
Study of Blockade of Subjective Opioid Effects, Pharmacokinetics, and Safety of Subcutaneous 
Injections of Depot Buprenorphine (RBP-6000) in Subjects with Opioid Use Disorder
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 30 September 2016. 


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Appendix 1 
Schedule of Events  
Procedure/Evaluation 
Screening1 
Inj 1 
Inj 2 
Inj 3 
Inj 4 
Inj 5 
Inj 6 
EOS/ 
ET 
Safety 
Follow-Up15 
EOS Visit 
RB-US-13-0003 
Screening Visit 
INDV-6000-301 
Day 1 
Week 1 
Day 29 
Week 5 
Day 57 
Week 9 
Day 85 
Week 13 
Day 113 
Week 17 
Day 141 
Week 21 
Day 169 
Week 25 
Day 197 
Week 29 
Window (Days) 
- - - - - - - - - Same Day Events3 - - - - - - - - - 
-2 / +7 
-2 / +7 
-2 / +7 
-2 / +7 
-2 / +7 
-2 / +7 
-2 / +7 
Informed Consent 2 
 
X 
 
 
 
 
 
 
 
 
IWRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
Vital Signs 4 
X 
 
X 5 
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy Test 6 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Urine Drug Screen 7 
X 
 
 
X 
X 
X 
X 
X 
X 
 
AE Assessment  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 8 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Injection Site Evaluation 9 
X 
 
 
X 
X 
X 
X 
X 
X 
 
RBP-6000 Injection 
 
 
X 
X 
X 
X 
X 
X 
 
 
Injection Site Grading Scale 10 
 
 
X 
X 
X 
X 
X 
X 
 
 
Injection Site Pain VAS 10 
 
 
X 
X 
X 
X 
X 
X 
 
 
Counseling / Behavioral Therapy 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Review of Treatment Options12 
 
 
 
 
 
 
X 
X 
X 
 
Physical Examination13 
X 
 
 
 
 
 
 
 
X 
 
Body Weight 
X 
 
 
 
 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
BMI (calculated in CRF) 
 
X 
 
 
 
 
 
 
X 
 
Hip and Waist Circumference 
X 
 
 
 
 
 
 
 
X 
 
Hip-to-Waist Ratio (calculated in CRF) 
 
X 
 
 
 
 
 
 
X 
 


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Procedure/Evaluation
Screening1
Inj 1
Inj 2
Inj 3
Inj 4
Inj 5
Inj 6
EOS/
ET
Safety
Follow-Up15
EOS Visit
RB-US-13-0003
Screening Visit
INDV-6000-301
Day 1
Week 1
Day 29
Week 5
Day 57
Week 9
Day 85
Week 13
Day 113
Week 17
Day 141
Week 21
Day 169
Week 25
Day 197
Week 29
Window (Days)
- - - - - - - - - Same Day Events3 - - - - - - - - -
-2 / +7
-2 / +7
-2 / +7
-2 / +7
-2 / +7
-2 / +7
-2 / +7
Hematology / Serum Chemistry 14
X
X
Urinalysis 14
X
X
AE = adverse event; BMI = body mass index; C-SSRS = Columbia Suicide Severity Rating Scale; EOS = End of Study; ET = Early Termination; Inj. = injection; 
IWRS=Interactive voice/web response system; NA = Not Applicable; VAS = Visual Analog Scale.
1.
All indicated screening assessments conducted during the RB-US-13-0003 EOS Visit will be used as part of the overall screening process for the present 
study.  However, required assessments indicated under “Screening Visit INDV-6000-301” must only be performed after the ICF is signed.
2.
The ICF may be shared with the subject up to 2 months before the EOS Visit for RB-US-13-0003 study in order to discuss this new study as a possible 
treatment option. However, the ICF for this study must not be signed until all assessments for the RB-US-13-0003 EOS Visit are complete.
3.
The Screening Visit assessments and Day 1 injection must occur on the same day as the RB-US-13-0003 EOS Visit. 
4.
Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. With 
the exception of Day 1, vital signs will be taken ≤ 60 minutes prior to injection, and 1 hour (± 30 minutes) post-completion of injection. 
5.
On Day 1, vital signs are only required to be collected 1 hour (± 30 minutes) post-completion of injection; the screening value will serve as the pre-
injection value.
6.
Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year).
7.
Oxycodone may not show up in all opiate assays and should be assessed separately.
8.
At the EOS Visit for Study RB-US-13-0003, the C-SSRS “since last visit” (e-PRO) version will be used for confirming exclusion 3 only.  In addition, as 
part of the Screening Visit for INDV-6000-301, the C-SSRS “baseline/screening” (paper) version will be required to be completed; on all other visits, 
the “since last visit” (paper) version should be used.  The C-SSRS “baseline/screening” assessment will include both a lifetime and past 6-month time 
interval.  
9.
Injection site will be evaluated for potential reaction and evidence of attempted removal before the next injection of RBP-6000 is administered.  
10. Local injection site grading will be performed 1 hour (± 30 minutes) post-completion of injection.
11. Injection Site Pain VAS will be completed by the subject 1 hour (± 30 minutes) post-completion of injection.
12. Subject’s alternative treatment options should be assessed at least two months before EOS, however it is recommended to review at each visit.
13. Brief physical examination including general appearance, chest/lungs, heart, abdomen and a brief neurological assessment.
14. Additional unscheduled labs may be added at the Investigator’s discretion in order to fully assess any AEs.
All subjects should receive a safety follow-up contact. Subjects should be contacted by telephone in order to inquire about any new AEs, or a stop date 
for any ongoing AEs or concomitant medications. They are not required to return to the site, unless the Investigator deems it medically necessary. In the 
event a subject cannot be contacted for the follow-up telephone contact, a minimum of 2 documented telephone calls followed by a certified mailed 
letter will be considered a reasonable effort for contacting the subject. If follow-up contact with a subject cannot be made, any open AEs will be 
designated as “ongoing.”


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Clinical Study Protocol:  INDV-6000-301
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Appendix 2
IMP Preparation, Administration, and Depot Removal 
Instructions
RBP-6000 PREPARATION AND DOSING PROCEDURE

100 MG BUPRENORPHINE

300 MG BUPRENORPHINE
IMPORTANT:  Only qualified study personnel can prepare the IMP. Protective gloves (latex 
or nitrile) should be worn when preparing and dosing RBP-6000.  Remove the product from the 
refrigerator at least 15 minutes before use to allow the product to reach room temperature before 
dosing.  Product may be left at room temperature up to 8 hours prior to use.  If product is not 
used that day, it should be marked appropriately.  
  
FOLLOW THE INSTRUCTIONS AS DIRECTED TO ENSURE PROPER DOSING
Preparation of the Product Prior to Administration: 
The following components will be used in the preparation of RBP-6000:
•
One sealed foil pouch containing a syringe pre-filled with RBP-6000 and an oxygen 
absorber pack. 
•
One sterile 19-gauge, 1- or 5/8-inch hypodermic safety needle
1. On a clean field, open the foil pouch and remove the contents. Discard the oxygen absorber 
pack. The pouch must be retained for accountability.
2. Un-cap the pre-filled RBP-6000 syringe and attach the safety needle cartridge by pushing in 
and turning the needle until it is finger tight. Do not strip the threaded fitting by over-
tightening the needle. Position the sheath at 90 degrees to the needle.  Pull off the needle 
cartridge cover.   More complete documentation on the usage of the SurGuard2 safety needle 
can be found in the included instruction sheet. 
3. While holding the syringe vertically with the tip upwards, expel air bubbles by stroking the 
plunger up and down.
4. The product is now ready for administration.  Carefully recap the needle.
Administration Procedure:
IMPORTANT: Once prepared (removed from foil pouch), the product must be 
administered within a maximum of 30 minutes.
Choose an injection site below the waist but above the hip bone; from where the body curves at 
the side to about 2 inches from the middle of the abdomen with adequate amounts of 
subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair.  Since you 
can vary the injection site with a subcutaneous injection, choose an area that has not recently 
been used.  


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Possible injection site locations and an injection rotation pattern are shown in Figure 2.  
Injections should be started based on where the last injection in RB-US-13-0003 was given.
Figure 2
Injection Locations
1. Cleanse the injection-site area with an alcohol swab.  
2. Using the thumb and forefinger of your non-dominant hand, grab and bunch the area of skin 
around the injection site.
3. Using your dominant hand, insert the needle quickly. If a 1-inch needle is used, enter half the 
length, if a 5/8-inch needle is used the needle may be inserted fully. The approximate angle 
you use will depend on the amount and fullness of the subcutaneous tissue and the length of 
the needle.
4. After the needle is inserted, release the skin with your non-dominant hand.
5. Pull back on the plunger to check for blood.  If blood is present in the syringe, do not inject.  
Withdraw the needle and dispose of syringe and needle in an appropriate waste container.  
Repeat the “Preparation of the Product Prior to Administration” procedures and the 
“Administration Procedure” using a different abdominal injection site with another syringe 
of RBP-6000 and associated components.
6. Inject the product using a slow, steady push. Press down on the plunger until the syringe is 
empty.
7. Withdraw the needle at the same angle used for insertion. Do not rub the injection area.  If 
there is bleeding, apply minimal pressure with a gauze pad or bandage.  Engage the safety 
sheath on the needle as per the SurGuard2 needle instructions.  
8. Dispose of used and unused syringe and needle in an appropriate waste container. 
Hipbones
Waist
1 / 5
2 / 6
3
4


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PROCEDURE FOR REMOVAL OF THE RBP-6000 DEPOT
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot.
The following surgical procedure should be followed:
1.
Palpate the depot and surrounding area to confirm its exact location.
2.
Cleanse the area with an antiseptic solution (e.g., Betadine).  
3.
Infiltrate the area with a local anesthesia (e.g., Lidocaine 1% or a lidocaine/adrenaline 
[epinephrine] mixture) and wait for it to take effect.
4.
Cover the area with a sterile drape.
5.
Incise the skin up to the subcutaneous tissues using a scalpel. 
6.
Using blunt and sharp dissection, identify the plane between the depot and surrounding 
subcutaneous tissues.  Once the plane is identified, separate the superficial 25% of the 
circumference of the depot with blunt dissection. 
7.
Gently lift the incised ellipse of skin and depot with forceps.  
8.
Once the depot is removed, ensure hemostasis, and close the skin with non-absorbable 
sutures.  
9.
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the SOP at the clinical site.


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Appendix 3
Prohibited Cytochrome P450 Inhibitors and Inducers
Cytochrome P450 3A4 Inhibitors
Name
Example Brand Name(s)
Name
Example Brand Name(s)
Amiodarone
Cordarone, Nexterone
Ketoconazole
Nizoral
Amprenavir
Agenerase, 
Metronidazole
Flagyl
Aprepitant
Emend
Mibefradil
Posicor
Chloramphenicol
Chloromycetin
Miconazole
Oravig
Cimetidine
Tagamet
Mifepristone
Mifeprex, Korlym
Ciprofloxacin
Ciloxan, Cipro
Nefazodone
Serzone
Clarithromycin
Biaxin
Nelfinavir
Viracept
Clotrimazole
Lotrimin
Nicardipine
Cardene
Cyclosporine
Neoral, Sandimmune
Norfloxacin
Noroxin
Delavirdine
Rescriptor
Norfluoxetine
Seproxetine (discontinued)
Diethyl-
dithiocarbamate
(zinc chelator used in cancer, 
no other name)
Propofol
Diprivan
Diltiazem
Cardizem, Dilacor 
Quinine
Qualaquin
Ethinyl estradiol
Apri, Aviane, Beyaz
Ritonavir
Norvir
Erythromycin
Erythrocin
Saquinavir
Invirase
Fluconazole
Diflucan
Sertraline
Zoloft
Fluoxetine
Prozac
Starfruit
Carambola, fruit of Averrhoa 
carambola
Fluvoxamine
Luvox
Telithromycin
Ketek
Gestodene
Progestogen hormonal 
contraceptive. 
Not available in the US. 
Troleandomycin
Not available in the US
Grapefruit juice
Grapefruit juice
Verapamil
Isoptin
Imatinib
Gleevec
Voriconazole
Vfend
Indinavir
Crixivan
Zafirlukast
Accolate
Itraconazole
Sporanox


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Cytochrome P450 3A4 Inducers
Name
Example Brand Name(s)
Name
Example Brand Name(s)
Barbiturates
   Nembutal, Luminal
Phenytoin
Dilantin, Phenytek
Carbamazepine
Carbatrol, TEGretol
Pioglitazone
Actos
Dexamethasone
Decadron
Primidone
Mysoline
Efavirenz
Sustiva, Atripla
Rifabutin
Mycobutin
Ethosuximide
Zarontin
Rifampin
Rifadin, Rimactane
Glucocorticoids
Prednisone, Medrol, 
Millipred
Hypericum 
perforatum
Medicinal herb 
Glutethimide
Doriden (Not available in 
US), Elrodorm, Noxyron.
Sulfadimidine
Not available in the US
Modafinil
Provigil
Sulfinpyrazone
Anturane
Nevirapine
Viramune
Troglitazone
Rezulin, Resulin 
Non available in US
Oxcarbazepine
Trileptal, Oxtellar XR 
Troleandomycin
Tao 
Not available in the US
Phenobarbital
Luminal 
Cytochrome P450 2C8 Inhibitors
Name
Example Brand Name(s)
Name
Example Brand Name(s)
Gemifibrozil
Lopid
Montelukast
Singulair
Trimethoprim
Primsol, Proloprim
Quercetin
Plant pigment (flavonoid)
Glitazones
Actos, Avandia
Cytochrome P450 2C8 Inducer
Name
Example Brand Name(s)
Name
Example Brand Name(s)
Rifampicin
Rifadin
Source:  http://medicine.iupui.edu/clinpharm/ddis/clinical-table/ Accessed 30 September 2016. 


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Indivior Inc.
Clinical Study Protocol:  INDV-6000-301
Amendment 1:  30 September 2016
Page 58 of 67
Confidential
Appendix 4
Columbia Suicide Severity Rating Scale (C-SSRS) --
Baseline/Screening Version


RBP-6000
Indivior Inc.
Clinical Study Protocol:  INDV-6000-301
Amendment 1:  30 September 2016
Page 59 of 67
Confidential
Note:  Screening assessment should include both a lifetime and “past 6-month” time interval.  


RBP-6000
Indivior Inc.
Clinical Study Protocol:  INDV-6000-301
Amendment 1:  30 September 2016
Page 60 of 67
Confidential
Appendix 5
Columbia Suicide Severity Rating Scale (C-SSRS) --  
Since Last Visit Version


RBP-6000
Indivior Inc.
Clinical Study Protocol:  INDV-6000-301
Amendment 1:  30 September 2016
Page 61 of 67
Confidential


RBP-6000
Indivior Inc.
Clinical Study Protocol: INDV-6000-301
Amendment 1:  30 September 2016
Page 62 of 67
Confidential
Appendix 6
Injection Site Grading Scale
Injection site 
Reactions
None
(Grade 0)
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening
(Grade 4)
Pain
None
Does not 
interfere with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily 
activity
Emergency room 
(ER) visit or 
hospitalization 
Tenderness
None
Mild discomfort 
to touch.
Discomfort with 
movement.
Significant 
discomfort at rest 
ER visit or 
hospitalization
Erythema/
Redness*
(quantitative)
None
2.5 – 5 cm
5.1 – 10 cm
> 10 cm
Necrosis or
exfoliative 
dermatitis
Induration **
None
2.5 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
Swelling **
(subjective)
None
2.5 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
Modified from:  
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 30 September 2016. 


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Indivior Inc.
Clinical Study Protocol: INDV-6000-301
Amendment 1:  30 September 2016
Page 63 of 67
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No Pain
Pain as bad 
as it could be
Appendix 7
Injection Site Pain Visual Analog Scale
How would you rate your injection site pain today?
             
Please answer the following question by checking the box with either a “Yes” or “No”:
Are you currently experiencing any burning or stinging at the injection site?
YES  
NO
Note:   Copies of any pre-printed VAS forms to be completed by a subject must be checked to 
confirm that the rating scale measures 100 mm (3.94 in) in length.


RBP-6000
Indivior Inc.
Clinical Study Protocol: INDV-6000-301
Amendment 1:  30 September 2016
Page 64 of 67
Confidential
Appendix 8
Elevated Liver Function Tests 
Elevated liver functions tests meeting one of the following criteria below must follow the 
outlined procedures. 
Criteria 1
ALT ≥3X ULN and <5X ULN 
+ Bilirubin <2X ULN
+ DO NOT exhibit hepatitis symptoms or rash

Contact the Indivior Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety.

Subject may continue study treatment, if liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) can be monitored weekly for up to 4 weeks.

If the subject later meets criteria 2 or 3, immediately withdraw study treatment, perform 
additional testing and continue safety follow–up until liver chemistries resolve, stabilize 
or return to baseline values.

After 4 weeks of monitoring, if ALT <3XULN and bilirubin <2XULN, subject must be 
monitored twice monthly until liver chemistries normalize or return to within baseline 
values.
Criteria 2
ALT ≥5X ULN 
or 
ALT ≥3X ULN 
+ Hepatitis symptoms or rash 
+ cannot be monitoring for 4 weeks or have elevations that persist ≥4 weeks

Subject must not receive any further injections of RBP-6000. 

Contact the Indivior Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety and any addition laboratory testing required. 

Make every reasonable attempt to have the subject return to the clinic within 24-72 hours 
for repeat liver chemistries and additional testing.

Monitor subject weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.


RBP-6000
Indivior Inc.
Clinical Study Protocol: INDV-6000-301
Amendment 1:  30 September 2016
Page 65 of 67
Confidential

Upon completion of the safety follow-up, the subject must be withdrawn from the study 
unless further follow–up is required.
Criteria 3
ALT ≥3X ULN + Bilirubin ≥2X ULN (>35% direct)
or
ALT ≥3X ULN + INR >1.5:
Note: INR testing is not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.

Subject must not receive any further injections of RBP-6000. 

Contact the Indivior Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety and any addition laboratory testing required. 

Make every reasonable attempt to have the subject return to the clinic within 24 hours for 
repeat liver chemistries, additional testing and close monitoring (with specialist or 
hepatology consultation recommended).

Monitor the subject twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.

Upon completion of the safety follow-up, the subject must be withdrawn from the study 
unless further follow–up is required.




RBP-6000
Indivior Inc.
Clinical Study Protocol: INDV-6000-301
Amendment 1:  30 September 2016
Page 67 of 67
Confidential
Appendix 10
Investigator’s Signature
Study Title:
An Open-Label, Depot Buprenorphine (RBP-6000) Treatment 
Extension Study in Subjects with Opioid Use Disorder
Study Number:
INDV-6000-301
Original Protocol: 
Amendment 1:
24 June 2016
30 September 2016
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
Signed:
Date:
Printed Name and Credentials:
Title:
Site Name:
Address:
Telephone:

SAP_001.pdf: 
 
 NCT02896296  
 
 
Study Number: INDV-6000-301  
 
 
Title: An Open-Label, Depot Buprenorphine (RBP-6000) Treatment Extension 
Study in Subjects With Opioid Use Disorder  
 
 
 
Statistical Analysis Plan Date: 06 October 2017 


 
Statistical Analysis Plan 
 
Sponsor: 
Indivior Inc.  
Protocol No: 
INDV-6000-301 
Protocol Version 
No./Date 
Amendment 1 / 30-Sep-2016 
Title 
An Open-Label, Depot Buprenorphine (RBP-6000) 
Treatment Extension Study in Subjects with Opioid Use 
Disorder 
CRF Version No./Date 
 5.0 / 17 Mar 2017 
SAP Version No./Date: 
1.0 / 06 Oct 2017 
 
Sponsor 
Sponsor Name: 
Indivior Inc. 
Biostatistics/ Title: 
 Associate Fellow 
Medical/Title: 
, Medical Monitor 
 
 
Quartesian 
 
Project Manager/Title: 
, Senior Statistical Programmer / Analyst 
Biostatistician / Title: 
, Manager in Biometrics  


1.0 
TITLE PAGE 
 
 
INDV-6000-301 
 
 
An Open-Label, Depot Buprenorphine (RBP-6000) Treatment Extension Study 
in Subjects with Opioid Use Disorder  
 
  
 
 
 
Final Version 1.0: October 6, 2017 
 
 
 
 
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. 


Indivior Inc. 
 
Page 1 
[INDV-6000-301] SAP v 1.0 
[October 6, 2017] 
 
2.0 
TABLE OF CONTENTS 
Statistical Analysis Plan ...................................................................................................................................1 
1.0 
TITLE PAGE .....................................................................................................................................2 
2.0 
TABLE OF CONTENTS ...................................................................................................................1 
3.0 
LIST OF ABBREVIATIONS ............................................................................................................4 
4.0 
INTRODUCTION ..............................................................................................................................6 
5.0 
OBJECTIVE .......................................................................................................................................8 
6.0 
SUBJECT POPULATIONS AND TREATMENT GROUPS ...........................................................9 
6.1 
Screened Population.............................................................................................................9 
6.2 
Safety Analysis Set ..............................................................................................................9 
6.3 
Treatment Groups ................................................................................................................9 
7.0 
SUBJECT DISPOSITION ...............................................................................................................10 
8.0 
PROTOCOL DEVIATIONS ............................................................................................................11 
9.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .........................................12 
9.1 
Substance use history .........................................................................................................12 
9.2 
Medical History .................................................................................................................12 
9.3 
Prior and Concomitant Medications ..................................................................................12 
10.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .................................................16 
10.1 
Extent of Exposure .............................................................................................................16 
10.2 
Injection Dose and Visit Compliance ................................................................................16 
11.0 
Exploratory EFFICACY ANALYSES .............................................................................................17 
11.1 
Urine Drug Screen (UDS) ..................................................................................................17 
12.0 
SAFETY ANALYSES .....................................................................................................................20 
12.1 
Adverse Events ..................................................................................................................20 
12.1.1 
Adverse Events ....................................................................................................20 
12.1.2 
Serious Adverse Events .......................................................................................21 
12.1.3 
Adverse Events Leading to Discontinuation .......................................................21 
12.1.4 
Deaths ..................................................................................................................22 
12.1.5 
Potentially Pertaining to Drug Withdrawal Symptoms .......................................22 
12.1.6 
Potentially Pertaining to Injection Site Reactions ...............................................22 
12.1.7 
Hepatic Disorders Topic of Special Interest ........................................................22 
12.1.8 
Central Nervous System Depression Topic of Special Interest ...........................22 
12.1.9 
Respiratory Depression Topic of Special Interest ...............................................22 
12.1.10 Acute Pancreatitis Topic of Special Interest........................................................22 
12.1.11 Orthostatic Hypotension Topic of Special Interest..............................................23 


Indivior Inc. 
 
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12.1.12 Psychiatry History Topic of Special Interest .......................................................23 
12.2 
Clinical Laboratory Parameters .........................................................................................24 
12.2.1 
Hematology .........................................................................................................25 
12.2.2 
Serum Chemistry .................................................................................................25 
12.2.3 
Urinalysis .............................................................................................................26 
12.3 
Vital Signs ..........................................................................................................................26 
12.4 
Other Safety Parameters ....................................................................................................26 
12.4.1 
Suicidality ............................................................................................................26 
12.4.2 
Local Injection Site Evaluation ...........................................................................27 
12.4.3 
Local Injection Site Tolerability ..........................................................................28 
12.4.4 
Injection Site Pain................................................................................................28 
12.4.5 
Other Safety Variables ........................................................................................28 
12.5 
Independent Drug Counseling/Behavioural Therapy ........................................................28 
13.0 
POOLED ANALYSES ....................................................................................................................29 
14.0 
SUBGROUP ANALYSES ...............................................................................................................30 
15.0 
HEALTH OUTCOME ANALYSES ...............................................................................................31 
16.0 
PLASMA CONCENTRATION ANALYSES .................................................................................32 
17.0 
INTERIM ANALYSIS.....................................................................................................................33 
18.0 
DETERMINATION OF SAMPLE SIZE.........................................................................................34 
19.0 
COMPUTER METHODS ................................................................................................................35 
20.0 
DATA HANDLING CONVENTIONS ...........................................................................................36 
20.1 
Reference Dates and Analysis Periods ..............................................................................36 
20.2 
Analysis visits and Other Definitions ................................................................................36 
20.3 
Derived Efficacy Variables ................................................................................................38 
20.4 
Repeated or Unscheduled Assessments of Safety Parameters ...........................................38 
20.5 
Missing Date of Investigational product ............................................................................38 
20.6 
Missing Severity and relationship to Study Drug in Adverse Events ................................38 
20.7 
Missing Date Information for Adverse Events ..................................................................38 
20.8 
Missing Date Information for Concomitant Medications ..................................................39 
20.9 
Character Values of Clinical Laboratory Parameters AND other Laboratory 
Imputation rules .................................................................................................................41 
20.10 
C-SSRS DATA IMPUTATION ........................................................................................41 
21.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ...........................................................42 
22.0 
REFERENCES .................................................................................................................................43 
23.0 
Appendix ..........................................................................................................................................44 
23.1 
Appendix 1: List of Preferred Terms from Standard MedDRA Queries for Adverse 
Events of Special Interest...................................................................................................44 
List of Preferred Terms for Psychiatric History ...............................................................................44 


Indivior Inc. 
 
Page 3 
[INDV-6000-301] SAP v 1.0 
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Customized MedDRA Query (CMQ) List of Preferred Terms for Drug Related Hepatic 
Disorders ............................................................................................................................51 
CMQ List of Preferred Terms for Injection Site Reaction ...............................................................54 
CMQ List of Preferred Terms for CNS Depression .........................................................................55 
CMQ List of Preferred Terms for Respiratory Depression/Respiratory Failure ..............................56 
CMQ List of Preferred Terms for Orthostatic Hypotension ............................................................57 
CMQ List of Preferred Terms for Withdrawal Symptoms...............................................................57 
CMQ List of Preferred Terms for Acute Pancreatitis ......................................................................58 
23.2 
Appendix 2: List of CYP3A4 Inhibitor Medications .........................................................58 
23.3 
Appendix 3: Tables, Figures and Listings .........................................................................60 
 


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3.0 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CDF 
Cumulative Distribution Function 
CNS 
Central nervous system 
CRF 
Case Report Form 
CTMS 
Clinical Trials Management System 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
EOS  
End of Study 
ET 
Early Termination 
GGT 
Gamma-glutamyl Transpeptidase 
HDL-C 
High-density lipoprotein -  Cholesterol 
IA 
Interim Analysis 
ICF 
Informed Consent Form  
IDC 
Individual Drug Counseling 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
Over The Counter 
PDV 
Protocol Deviation 
PT 
Preferred Term 
OUD 
Opioid Use Disorder 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SDTMIG 
Study Data Tabulation Model Implementation Guide 
SI 
International System 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Event 
TBIL 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Listings, and Figures 
UDS 
Urine Drug Screen 


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ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WHODRUG 
World Health Organization Drug Dictionary 


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4.0 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
final reporting and analyses of data collected for the full study (Protocol INDV-6000-301).  
This SAP should be read in conjunction with the study protocol and case report form 
(CRF). This version of the plan has been developed using the protocol dated 30SEP2016 
and CRF dated 17Mar2017.  
This is a multicenter, open-label, RBP-6000 treatment extension study in which 
approximately 300 subjects diagnosed with moderate to severe Opioid Use Disorder 
(OUD) will be enrolled. Enrollment is defined as the first dose of RBP-6000 administered 
for this study. Only subjects who have completed the End of Study (EOS) procedures for 
Study RB-US-13-0003, have signed the INDV-6000-301 informed consent form (ICF), 
and meet all enrollment criteria will be considered for inclusion in this study. 
The Institutional Review Board (IRB) approved ICF may be shared with the potential 
subject up to 2 months before the EOS Visit for Study RB-US-13-0003 to discuss this study 
as a possible treatment option. However, the ICF for Study INDV-6000-301 must not be 
signed until all assessments for the RB-US-13-0003 EOS Visit are complete. 
The RB-US-13-0003 EOS assessments completed at the EOS Visit will serve as part of the 
screening assessments for this study. In addition, medical history will be collected, height 
measured, and subjects will be requested to complete a Columbia Suicide Severity Rating 
Scale (C-SSRS) baseline survey.  
On Day 1 (the date of the first injection), eligible subjects will receive a subcutaneous (SC) 
injection of RBP-6000. For each injection, subjects may receive either 100 mg or 300 mg 
of RBP-6000 (to be referred to as 100/300 Flex for the remainder of this document), based 
on the medical judgment of the investigator. Following RBP-6000 injection, vital signs and 
the injection site will be assessed. The injection site will be assessed by the site for pain, 
tenderness, erythema/redness, induration and swelling using a 5-point severity scale (the 
Injection Site Grading Scale). In addition, the subject will assess their own injection site 
pain using a visual analog scale (VAS) (referred to as the Injection Site Pain VAS). Before 
departing the site, the subject will also be assessed for adverse events (AEs) and use of 
concomitant medications. 
Subjects will not be permitted to receive supplemental buprenorphine during the RBP-6000 
treatment period (Day 1 to EOS/ET Visit). Subjects who require supplemental 
buprenorphine pharmacotherapy during the RBP-6000 treatment period will be withdrawn 
from the study and referred for appropriate treatment. 
Subjects will return to the site for monthly injection visits every 28 days (-2 / +7 days) for 
a total of up to 6 injections. Subjects are not required to complete all 6 injections and may 
choose to “early terminate” (ET) the study at any time. 


RBP-6000 
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At each subsequent visit (Injection Visits 2 through 6) the following procedures and 
assessments will be performed: urine pregnancy test for all female subjects who are of 
childbearing potential before each injection; evaluation of previous injection site for 
potential reaction and evidence of attempts to remove the depot; collection of vital signs 
pre- and post-injection; RBP-6000 injection; urine drug screen (UDS); C-SSRS since last 
visit, counseling (manual-guided behavioral therapy); local injection site grading; subject 
self-assessment of injection site pain (Injection Site Pain VAS); use of concomitant 
medications; and assessment for AEs. Laboratory tests (hematology, chemistry and 
urinalysis) may be requested by the investigator on an ad-hoc basis as necessary to further 
examine any AEs. 
Alternative treatment options should be assessed at least two months before EOS at each 
visit, however it is recommended where possible to assess at every visit. 
At the EOS/ET Visit, the following procedures and assessments will be performed: 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; 
vital sign measurements; UDS; C-SSRS since last visit, counseling (manual-guided 
behavioral therapy); use of concomitant medications; assessment for AEs; brief physical 
exam; body weight measurement (to determine a subject’s body mass index [BMI]); hip 
and waist circumference measurement (to determine a subject’s hip-to-waist ratio); and 
laboratory tests (hematology, chemistry, urinalysis). 
Approximately 4 weeks after EOS/ET Visit, all subjects should be contacted by telephone 
or face-to-face visit safety follow-up assessment of AEs and use of any concomitant 
medications. 


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5.0 
OBJECTIVE 
Indivior is developing RBP-6000, a long-acting formulation of buprenorphine for monthly 
subcutaneous (SC) injection, for the treatment of Opioid Use Disorder (OUD). 
The objective is to provide ongoing treatment with RBP-6000 and safety monitoring for 
subjects who complete the RB-US-13-0003 study and for whom a new treatment venue 
has not been identified or arranged. 


RBP-6000 
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October 6, 2017 
6.0 
SUBJECT POPULATIONS AND TREATMENT GROUPS 
6.1 
SCREENED POPULATION 
The Screened Population Set includes any subject who signed the informed consent form. 
6.2 
SAFETY ANALYSIS SET 
The Safety Analysis Set consists of all subjects who received at least one dose of RBP-
6000. 
6.3 
TREATMENT GROUPS 
There is only one treatment group in the trial and all subjects will be labeled with “RBP-
6000 (100/300 mg Flex)”. 
 
 


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7.0 
SUBJECT DISPOSITION 
The number and percentage of subjects screened and screen failures, if any, will be 
summarized. 
The number and percentage of subjects who entered the RBP-6000 treatment period (i.e., 
Treatment Period, and see definition in Section 20.1), and who completed the study will be 
presented, together with the number and percentage of subjects who prematurely 
discontinued from the RBP-6000 treatment period along with reasons for study 
discontinuation will be summarized. 
In summary, it is that the following number and percentage of subjects will be presented: 
o All subjects who were considered screen-failures 
o All subjects who entered the RBP-6000 treatment period (i.e., Treatment 
Period, and see definition in Section 20.1) 
▪ All subjects who completed the study 
▪ All subjects who prematurely discontinued from the RBP-6000 
treatment period along with reasons for study discontinuation. 
 
The number and percentage of subjects included in each analysis set will be presented. 
A listing of the inclusion/exclusion reasons for screen failures will be provided, if any. 


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8.0 
PROTOCOL DEVIATIONS 
A listing of important protocol deviations (PDV) will be presented by subject using the 
Safety Analysis Set.  An important deviation is defined as: 
• Subject was deemed eligible for the study but did not meet inclusion/exclusion 
criteria  
• Consent was not obtained from the subject 


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9.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristics (sex, ethnicity, race, age [years and categories of 
≥18-<30, ≥30-<45, ≥45-<60, ≥60 and ≥65], weight [kg], height[cm], waist[cm], hip[cm], 
waist-to-hip ratio and body mass index [BMI; kg/m2]) will be summarized using 
descriptive statistics for subjects in the Safety Analysis Set.  Qualitative variables (sex, 
ethnicity, race, age categories, BMI categories) will be summarized using frequencies 
while quantitative variables (age, weight, height, BMI, waist, hip and waist-to-hip ratio) 
will be summarized using mean, SD, median, minimum, and maximum.  Demographic and 
baseline data will also be listed for all subjects. 
9.1 
SUBSTANCE USE HISTORY  
Substance use history will be presented by substance and previous use for subjects in the 
Safety Analysis Set. Tobacco use [never, former, current], caffeine use [never, former, 
current], alcohol use [never, former, current]) will be summarized using descriptive 
statistics for subjects in the Safety Analysis Set. Qualitative variables (tobacco use, caffeine 
use, alcohol use) will be summarized using frequencies.  
9.2 
MEDICAL HISTORY 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.0 and summarized by the number and percentage of subjects in each 
System Organ Class (SOC), Preferred Term (PT) and in the Safety Analysis Set. Subjects 
will be counted only once for each PT, only once at the System Organ Class (SOC), and 
only once at subject level for the counting of total number of subjects with a medical history 
term. Counts will be presented in descending frequency unless otherwise specified. 
Listings of medical history events for each subject will be provided. 
9.3 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be categorized by preferred name and drug 
category class (CMCLAS, ATC level 4 class per World Health Organization Drug 
Dictionary [WHODRUG]); and will be summarized for the Safety Analysis Set. The 
number and percentage of subjects using each medication will be displayed together with 
the number and percentage of subjects using at least one medication.  
 
Prior medications rolling over from prior studies will be considered for both prior and 
concomitant medications in this study.   
 Prior Medications 
For a subject in the Safety Analysis Set, prior medications will include any medication 
taken within 28 days prior to subject’s first dose of RBP-6000 in the INDV-6000-301 
study.   


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Concomitant Medications 
Concomitant medications are defined as prescribed medications and Over The Counter 
(OTC) preparations, including herbal preparations and vitamins, other than RBP-6000. 
All prior medications will be presented in separate listing for the Safety Analysis Set. 
A summary of all concomitant medications taken from Day 1 to last dose + 28 days will 
be presented as during RBP-6000 dosing for the Safety Analysis Set. 
A summary of all concomitant medications taken from the last dose + 29 days to the last 
recorded assessment will be presented as post RBP-6000 dosing for the Safety Analysis 
Set. 
A listing of all subject’s concomitant medications during RBP-6000 dosing and post RBP-
6000 dosing will be listed separately.  
After imputing the incomplete start/end date of non-study medications (as described in 
Section 20.8), the determination of concomitant medication during vs. post RBP-6000 
dosing follows the rules in the Table 1 below.  
Table 1: Determination of Concomitant Medication during vs. Post RBP-6000 doing 
 
 
Start date of Non-Study Medication 
 
 
missing 
Prior to day 1 
from Day 1 to last 
dose +28 days 
(inclusive) 
Post last 
dose+28 days 
End date of 
non-study 
medication 
missing 
During1, 
Post2 
During, Post 
During, Post 
Post  
from Day 1 to last 
dose +28 days 
(inclusive) 
During 
During  
During  
Data error 
 Post last dose+28 
days 
During, 
post 
During, post 
During, post 
post 
1 during RBP-6000 dosing. 2 post RBP-6000 dosing 
 
CNS Depressants 
If a subject satisfies any of the three criteria below, then the subject is classified as taking 
a CNS Depressant 
Criterion 1: 


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Subject with concomitant medication and its class (CMCLAS) in ('BENZODIAZEPINE 
RELATED 
DRUGS' 
'BENZODIAZEPINE 
DERIVATIVES' 
'DIAZEPINES, 
OXAZEPINES, THIAZEPINES AND OXEPINES' 'OTHER HYPNOTICS AND 
SEDATIVES' 'PHENOBARBITAL'). Defined in the later section (CNS Depressant 
Medication Categories) 
Criterion 2: 
Subject with substances 'Barbiturates' or 'Benzodiazepine' detected positive in Urine Drug 
Screen during the Treatment Period. 
CNS Depressant Medication Categories 
Benzodiazepine-related drugs 
If the Concomitant medication class is “BENZODIAZEPINE RELATED DRUGS” or 
detection of substances “Benzodiazepine” positive in Urine Drug Screen positive during 
the Treatment Period, then it is derived as Benzodiazepine related drugs. 
Benzodiazepine derivatives 
If the Concomitant medication class contains (“BENZODIAZEPINE DERIVATIVES”, 
“DIAZEPINES, OXAZEPINES, THIAZEPINES AND OXEPINES”) during the 
Treatment Period then it is derived as Benzodiazepine Derivatives. 
Other Hypnotics and Sedatives  
If the Concomitant medication class is (“OTHER HYPNOTICS AND SEDATIVES”) 
during the Treatment Period, then it is derived as Other Hypnotics and Sedatives. 
Phenobarbital and Derivatives 
If the Concomitant medication class is “PHENOBARBITAL” during RBP-600 dosing or 
detection of substances Barbiturates positive in Urine Drug Screen during the Treatment 
Period, then it is derived as Phenobarbital and Derivatives. 
Summary of subjects who have taken CNS depressant medications during RBP-6000 
dosing (from Day 1 to last dose + 28 days) be provided. CNS depressant medications can 
be indemnified from two sources in this study: Concomitant medications or Urine Drug 
Screen as in the table below (Table 2). 


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Table 2: Summary of Subjects Who Have Taken CNS Depressant Medications During RBP-6000 
Dosing  
Any CNS depressant (from Concomitant medications) taken with a start 
date after Day 1 to last dose + 28 days 
Benzodiazepine-related Drugs  
Benzodiazepines Derivatives  
Other Hypnotics and Sedatives  
Phenobarbital and Derivatives  
Any positive CNS depressant (from UDS) during the treatment period 
Barbiturate Positive  
Benzodiazepines Positive  
 
Preferred terms at drug class ATC level 3 of drug categories Benzodiazepine-related Drugs, 
Benzodiazepines Derivatives, Other Hypnotics and Sedatives and Phenobarbital and 
Derivatives will be summarized in the safety analysis set (see Appendix 1 for the list of 
CNS depressant medications).  
A separate table for CNS depressant medications will be summarized for post RBP-6000 
dosing 
CYP3A4 Inhibitor Medication Categories 
The following four categories (Unclassified, Weak, Moderate and Strong) are used from 
Appendix 2 containing Generic/Brand name of the CYP3A4 Inhibitor medication and its 
categories.  
Preferred terms at drug class ATC level 3 of CYP3A4 Inhibitor Medications (Unclassified, 
Weak, Moderate or Strong inhibitors) during RBP-6000 dosing and post RBP-6000 dosing 
will be summarized in separate tables.  
 
 


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10.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
10.1 
EXTENT OF EXPOSURE  
Exposure duration is defined as the date of last injection + 28 days - the date of first 
injection +1.  
A summary of the exposure to RBP-6000 during the treatment period will be summarized 
by visit and dosage for the Safety Analysis Set. A listing of RBP-6000 exposure 
(administration/dispensation) will be provided. 
The duration of exposure in 4 week intervals (i.e., 0 - <4 weeks, 4 - <8 weeks through 20  
- <24 weeks and >= 24 weeks), total number of RBP-6000 doses received, the total number 
of actual doses as a continuous summary, and the total number of actual doses as a 
categorical summary will be presented by dose received in the Safety Analysis Set.  RBP-
6000 exposure data will also be listed detailing the dose of RBP-6000 received at each 
injection and days since last injection. Besides, the cumulative frequency distribution  will 
be tabulated by categories of >0 weeks, >=4 weeks through >=24 weeks.  
The number of subjects who had an early surgical removal of the RBP-6000 depot will be 
presented for the Safety Analysis Set and by dose level (i.e., either 100 mg or 300 mg).  
Early surgical removal of the study drug depot data including the reason and surgical 
removal date and time will be listed, if surgical removal of the RBP-6000 depot occurs 
within the study. 
10.2 
INJECTION DOSE AND VISIT COMPLIANCE 
Number and percentage of subjects with injection administrated at each visit will be 
tabulated in the Safety Analysis Set. Cumulative frequency distribution of injections will 
be summarized.  
Dose level frequency distribution (either 100 mg or 300 mg) at each visit will be 
summarized. Dose level over time during the treatment period for subjects who received 
100 mg at the first injection and 300 mg at the first injection will be summarized 
respectively in the Safety Analysis Set.  
Dose modification and its reason (adverse event, lower dose strategy or other) over time 
will be summarized and its distribution per visit will be plotted using stacked-bar plot. 
Listing of all subjects who experienced dose adjustments should be provided, including 
dose prior to and after dose adjustment, and reason for dose adjustment. 
Days since last injection will be summarized in the safety analysis set and the distribution 
of the relative study days of injections will be plotted and listed.  


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11.0 
EXPLORATORY EFFICACY ANALYSES 
11.1 
URINE DRUG SCREEN (UDS) 
 
The urine sample collected at Screening visit will be tested for drugs listed in the Table 3. 
The drugs classified as opioids are identified in the same table. 
Table 3: Opioid Drug Classification in Urine Drug Screen at Screening Visit. 
Drug 
Opioid? 
Amphetamine 
No 
Barbiturates 
No 
Benzodiazepine 
No 
Benzoylecgonine (Cocaine metabolite) 
No 
Cannabinoids 
No 
Opiates 
Yes 
Codeine 
Yes 
Hydrocodone 
Yes 
Hydromorphone 
Yes 
Methadone 
Yes 
Morphine 
Yes 
Oxycodone 
Yes 
Oxymorphone 
Yes 
Methamphetamine 
No 
Phencyclidine 
No 
 
At Screening, specific substances were confirmed once the test for Opiates was positive.  
The UDS for Opioids at Screening will be defined as follows: 
The UDS for Opioids is Non-negative at Screening if at least one UDS result (listed in 
Table ) is positive; 
The UDS for Opioids is Negative at Screening, if all non-missing UDS results for opioids 
are negative.  
If all UDS measurements for opioids are missing at Screening, the UDS for Opioids will 
be classified as missing; then be imputed as Non-negative; and be flagged as “Non-
Responder Imputation”.  


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The urine sample collected at visits in the Treatment Period will be tested for drugs listed 
in the Table 4. The drugs classified as opioids are identified in the same table. 
Table 4: Opioid Drug Classification in Urine Drug Screen at visits in the Treatment Period 
Drug 
Opioid? 
Amphetamine 
No 
Barbiturates 
No 
Benzodiazepine 
No 
Benzoylecgonine (Cocaine metabolite) 
No 
Cannabinoids 
No 
Opiates 
Yes 
Methadone 
Yes 
Oxycodone 
Yes 
Methamphetamine 
No 
Phencyclidine 
No 
 
Different from Screening Visit, specific opiate substances were not confirmed when the 
Opiates test was positive. Samples were tested for Oxycodone and Methadone separately 
from the Opiates test. 
 
The UDS for Opioids at visits in the Treatment Period will be defined as follows: 
The UDS for Opioids is Non-negative at visits in the Treatment Period if at least one 
UDS result (listed in Table 4; either the Opiates test, or individual test for Methadone or 
individual test for Oxycodone) is positive; 
The UDS for Opioids is Negative at visits in the Treatment Period, if all non-missing 
UDS results for opioids are negative.  
If all UDS measurements for opioids are missing at visits in the Treatment Period, the 
UDS for Opioids will be classified as missing; and then be imputed as Non-negative; and 
be flagged as “Non-Responder Imputation”.  
  
The percentage of UDS Negative for Opioids during the Treatment Period (i.e., only for 
scheduled visits in the Treatment Period) will be calculated by subject, as the number of 
visits with UDS Negative for Opioid for that subject divided by the number of scheduled 
visits during the Treatment Period. Note that this means that subject missing UDS for 
Opioids for any scheduled visit will be classified as Non-negative for that visit.  
The subject-specific percentage of UDS Negative for opioids will be summarized using 
Descriptive statistics (n, mean (SD), median, min and max). The cumulative distribution 
function (CDF) will be tabulated for the following categories: >=0%, >=10%, >=20% 
through 100%.   
  
A subject is classified as ‘treatment success’, if his/her percentage of UDS Negative for 
Opioids is >=80% during the Treatment Period. The Number and percentage of treatment 
successes will be summarized 
 
The number and percentage of subjects with UDS Negative for Opioids by visit at 
Screening/Baseline or during the Treatment Period will be summarized. The denominator 


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of the percentage will be the number of subjects in the Safety Analysis Set. Additionally, 
the percentage of subjects with UDS Negative for Opioids by visit will also be calculated 
using the available data approach, where the subjects missing UDS for Opioids for a visit 
will be excluded from the denominator of the percentage for that visit.  
The number and percentage of subjects with positive UDS results will be summarized for 
the substances tested or for Opiates test during the Treatment Period. The subject will be 
classified as positive for available substance/Opiates if the UDS result for that 
substance/Opiates is reported as positive at least once during the Treatment Period. Note 
that the subjects are only counted once for each substance or for the Opiates test.  
All drugs detected in the UDS tests (either Negative or Non-negative) for each subject, for 
all visits (scheduled or unscheduled), will be listed.  
 
 
 
 
 


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12.0 
SAFETY ANALYSES 
All analyses will be conducted by Analysis Period (s) over time at each analysis visit or 
overall in the Safety Analysis Set. Please see definition for Analysis Period and Analysis 
Visit in Section 20.1 and 20.2 respectively. 
The following variables will be evaluated to assess the safety and tolerability of RBP-6000: 
• Incidence of treatment-emergent adverse events (TEAEs). 
• Changes in clinical laboratory results.  
• Vital sign measurements. 
 
Other Safety Variables are: 
• Medical history. 
• Urine pregnancy test. 
• Suicidality using the C-SSRS. 
• Prior and concomitant medications. 
• Local injection site tolerability (e.g., injection site grading). 
• Injection site pain using a subject-reported VAS. 
• Weight, BMI, waist circumference, hip circumference and waist-to-hip ratio. 
• Behavioral therapy. 
 
12.1 
ADVERSE EVENTS 
12.1.1 
Adverse Events 
Imputation rules for AE (for determination of TEAE only) start date are in Section 20.7. 
Treatment-emergent Adverse Events (TEAEs) 
TEAEs are those that started following the first dose of RBP-6000 and before the 
Treatment End Date (the maximum of the date of the end-of-study/ Early Termination 
(EOS/ET) visit and the date of last injection + 28 days) in this study, or were present 
prior to the first dose of RBP-6000 regardless of causality and increased in severity 
within the treatment period (defined in section 20.1)  AEs include those events that are 
ongoing at the time a subject rolls-over from the RB-US-13-0003. 
Treatment-related Adverse Events 


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A summary of TEAEs will be presented for the Safety Analysis Set, including the number 
and percentage of subjects reporting at least one TEAE, the number and percentage of 
subjects with the following: 
• Related TEAEs 
• SAEs 
• Related SAEs 
• TEAEs with an outcome of death 
• TEAEs 
• Severe TEAEs 
• TEAEs leading to RBP-6000 discontinuation 
 
A breakdown of the number and percentage of subjects reporting each TEAE categorized 
by SOC and PT coded per the MedDRA dictionary version 19.0 will be presented in the 
Safety Analysis Set. Note that counting will be by subject not by event and subjects will 
be only counted once within each SOC or PT.   
A further tabulation of events experienced by ≥5% of subjects by SOC and PT will be 
presented for the Safety Analysis Set. If there are no TEAEs experienced ≥5% of subjects 
by any PT, this table will be empty. 
A summary of events reported, categorized by severity, will also be provided. Subjects 
with multiple events within a SOC or PT will be counted under the category of their most 
severe event within that SOC or PT.  A further tabulation of severe AE/TEAEs will be 
presented by SOC and PT. 
Additionally, treatment-related AEs/TEAEs will be summarized by maximum severity 
(mild, moderate, or severe). A breakdown of severe treatment-related AEs/TEAEs by SOC 
and PT will be provided. 
All AEs (including non-TEAEs) recorded on the CRF will be listed. 
12.1.2 
Serious Adverse Events 
SAEs and treatment-related SAEs will be summarized separately by SOC and PT for the 
Safety Analysis Set. 
All SAEs recorded on the CRF will be listed for all subjects. 
12.1.3 
Adverse Events Leading to Discontinuation 
A summary of AEs/TEAEs and treatment-related AEs/TEAEs leading to discontinuation 
(defined as an event with an outcome of ‘drug withdrawn’ in the CRF) will be provided, 
grouped by SOC and PT, for the Safety Analysis Set.  Supportive listings will be provided. 


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All AEs leading to discontinuation recorded on the CRF will be listed.  Additionally, 
TEAEs leading to dose reduction will be listed. 
12.1.4 
Deaths 
A table presenting the number and percentage of subjects who died during the Treatment 
Period will be presented for the Safety Analysis Set, respectively.  Deaths occurring in the 
study will also be listed for all screened subjects, if death occurs within the study. 
12.1.5 
Potentially Pertaining to Drug Withdrawal Symptoms  
A summary of TEAEs potentially pertaining to drug withdrawal during the Treatment 
Period, as defined in Appendix 1, will be summarized by SOC and PT for the Safety 
Analysis Set. 
Additionally, A summary table of Adverse Events potentially pertaining to drug 
withdrawal during the Safety Follow-up Period will be used to tabulate AEs related to drug 
withdrawal symptoms in the Safety Follow-Up period after EOS/ET visit, if any.   
12.1.6 
Potentially Pertaining to Injection Site Reactions 
A summary of TEAEs potentially pertaining to injection site reactions, as defined in 
Appendix 1, will be summarized by SOC and PT for the Safety Analysis Set. 
12.1.7 
Hepatic Disorders Topic of Special Interest 
A summary of TEAEs potentially related to hepatic disorders, as defined in Appendix 1, 
will be summarized by SOC and PT for the Safety Analysis Set. 
12.1.8 
Central Nervous System Depression Topic of Special Interest 
A summary of TEAEs related to Central Nervous System Depression, as defined in 
Appendix 1, will be summarized by SOC and PT for the Safety Analysis Set. 
12.1.9 
Respiratory Depression Topic of Special Interest 
A summary of TEAEs related to respiratory depression, as defined in Appendix 1, will be 
summarized by SOC and PT for the Safety Analysis Set. 
12.1.10 
Acute Pancreatitis Topic of Special Interest 
A summary of TEAEs related to acute pancreatitis as defined in Appendix 1, will be 
summarized by SOC and PT for the Safety Analysis Set. 


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12.1.11 
 Orthostatic Hypotension Topic of Special Interest 
A summary of TEAEs related to orthostatic hypotension, as defined in Appendix 1, will be 
summarized by SOC and PT for the Safety Analysis Set. 
12.1.12 
Psychiatry History Topic of Special Interest 
A summary of TEAEs regarding psychiatry history, as defined in Appendix 1, will be 
summarized by SOC and PT for the Safety Analysis Set. 
 
 
 
 
 
 
 
 
 
 
 
 


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12.2 
CLINICAL LABORATORY PARAMETERS 
Laboratory data will be reported using International System (SI) units (and using original 
units for some parameters if necessary) as collected by the central laboratory. Unless 
otherwise specified, all continuous laboratory data will be summarized using descriptive 
statistics (n, mean, SD, median, min and max) for each scheduled study assessment as well 
as change from baseline and percentage change from baseline [if applicable] by parameter 
class (hematology, chemistry, and urinalysis).  All laboratory assessments include a 
baseline summary as defined in Section 20.2 unless otherwise indicated. Hematology 
chemistry and urinalysis data will be summarized by displaying shifts from baseline value 
to EOS/ET visit.  All laboratory assessments will be listed by panel with the corresponding 
normal ranges for each parameter.  Screening laboratory tests will also be listed.  
The peak total bilirubin [x ULN] vs. peak aspartate aminotransferase (or peak alanine 
aminotransferase) [x ULN] on a log/log scale during the Treatment Period will be plotted 
in the Safety Analysis Set. And the box plot to access clinical liver safety data by maximum 
change from baseline during the Treatment Period will be plotted for lab tests ALT, AST 
and total bilirubin. 
Summary of potential hepatotoxicity for serum chemistry by type of criterion (shown in 
Table 5) and by analysis visit and at any time post baseline will be tabulated for the Safety 
Analysis Set. For “Any time post baseline”, a subject will be classified to their 
highest/worst applicable toxicity grade per criterion, among the post baseline visits 
including unscheduled visits, and be counted only once in the category corresponding to 
the worst grade. For subjects who met the criteria for potential hepatotoxicity (any time 
post baseline), their test results for ALT, AST, TBIL, ALP during study (i.e., at all 
scheduled and unscheduled visit) will be provided in a listing. 
 
 
 
 
 
 
 
 
 


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Table 5: Criteria for Potential Hepatotoxicity Laboratory Value 
Criteria 
ALT > 3 x ULN to < 5 x ULN 
ALT ≥ 5 x ULN to < 8 x ULN 
ALT ≥ 8 x ULN 
 
AST > 3 x ULN to < 5 x ULN 
AST ≥ 5 x ULN to < 8 x ULN 
AST ≥ 8 x ULN 
 
ALT & AST > 3 x ULN to < 5 x ULN 
ALT & AST ≥ 5 x ULN to < 8 x ULN 
ALT & AST ≥ 8 x ULN 
 
TBIL > 2 x ULN to < 5 x ULN 
TBIL ≥ 5 x ULN 
 
HYs Law: (all must be met to meet Potential Hy’s law) 
ALT or AST > 3 x ULN 
TBIL > 2 x ULN 
ULN < Alkaline phosphatase (ALP) < 2xULN 
 
12.2.1 
Hematology 
Parameters include hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, platelet count (available 
at EOS/ET only), red blood cell count and white blood cell count with differential.  Visits 
include Screening (or EOS Visit RB-US-13-0003) and Day 169 Week 25 (EOS INDV-
6000-301) /ET visit. 
12.2.2 
Serum Chemistry 
Parameters include albumin, ALP, ALT, amylase, AST, blood urea nitrogen, calcium, 
calculated creatinine clearance, carbon dioxide, chloride, creatinine, creatinine kinase and 
subtypes, gamma-glutamyl transferase, globulin, glucose (non-fasting), high-density 
lipoprotein, lactate dehydrogenase, lipase, low-density lipoprotein, magnesium, 
phosphorus, potassium, sodium, total bilirubin, direct bilirubin, total cholesterol, total 
protein, triglycerides and uric acid.  Visits include EOS Visit RB-US-13-0003 and Day 169 
Week 25 (EOS INDV-6000-301)/ET visit. 
 


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12.2.3 
Urinalysis 
Parameters include appearance, bilirubin, color, glucose, ketones, leucocyte esterase, 
nitrite, occult blood, pH, protein, specific gravity and urobilinogen. 
Microscopic examination of sediment will be performed only if the results of the urinalysis 
evaluation are positive. Microscopic examination also includes but not limited to WBC 
count, RBC count, casts, and crystals. The microscopic results will be listed only.  
 
12.3 
VITAL SIGNS 
Measurements of vital signs (supine blood pressure systolic, supine blood pressure 
diastolic, pulse rate, oral temperature, respiratory rate, pulse oximetry, weight, height, 
BMI, hip circumference, waist circumference and waist-to-hip ratio) will be summarized 
using descriptive statistics at each scheduled visit and time point including change from 
baseline, percentage change from baseline and pre- and post- injection change if available.   
Listings/tables of all vital sign assessments will be provided for the following groups: 
 
• Supine blood pressure systolic, Supine blood pressure diastolic, Pulse rate, Oral 
temperature, and Respiratory rate, Pulse Oximetry; 
• Body weight, BMI, Hip Circumference, Waist Circumference and Waist-to-hip 
ratio. 
 
 
12.4 
OTHER SAFETY PARAMETERS 
12.4.1 
Suicidality 
A listing of all results will be presented for all subjects for all visits.  
Table summaries will be run twice with two different baseline definitions: 
• “Baseline Lifetime” will use the answers for suicidality (lifetime) in the 
screening/baseline questionnaire.  
• “Baseline 6 months” will use the answers for suicidality (in the past 6 months) in 
the screening/baseline questionnaire. 
Suicidal Ideation Severity Scoring 


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The suicidal ideation score ranges from 0 to 5 and depends on the answers to the suicidal 
ideation portion of the C-SSRS.  The score is the maximum suicidal ideation category (in 
the following order: 1 = wish to be dead, 2 = non-specific active suicidal thoughts, 3 = 
active suicidal ideation with any methods (not plan) without intent to act, 4 = active suicidal 
ideation with some intent to act, without specific plan, and 5 = active suicidal ideation with 
specific plan and intent) present at the assessment.  If none of these questions are YES, 
then the suicidal ideation score is 0. 
Suicidal Ideation Intensity Scoring 
The suicidal ideation intensity score is the sum of the five intensity item scores to create a 
total score (range 0 to 25). The five intensity items include frequency, duration, 
controllability, deterrents and reason for ideation. Each item is scored from 0 to 5 with 5 
representing the most severe intensity.  
Suicidal Behavior Scoring 
The suicidal behavior score ranges from 0 to 5 and depends on the answers to the suicidal 
behavior portion of the C-SSRS.  The score is the maximum suicidal behavior category (in 
the following order: 1 = preparatory acts or behavior, 2 = aborted attempt, 3 = interrupted 
attempt, 4 = actual attempt, and 5 if the subject has an AE with a preferred term of 
completed suicide.  If none of these questions are YES and the subject does not have an 
AE with a preferred term of completed suicide, then the suicidal behavior score is 0. 
Suicidal ideation and suicidal behavior responses (Yes/No) will be summarized by analysis 
visit using counts and percentages in the Safety Analysis Set. Shift tables to demonstrate 
changes in C-SSRS categories and changes in suicidal ideation and behavior scores from 
baseline during the Treatment Period will be presented. CSSRS and suicidal ideation 
responses will be listed separately. The suicidal ideation intensity ratings, each of the five 
items and the total score of the intensity for subjects with an ideation will be listed. 
12.4.2 
Local Injection Site Evaluation 
The local injection site will be evaluated for potential reaction and evidence of any attempts 
by the subject to remove RBP-6000 following a previous injection. A summary table and 
a listing will be provided. Attempted removal results will be summarized by percentage of 
subjects with attempted removal in each dose received at each visit. 
 


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12.4.3 
Local Injection Site Tolerability 
Local injection site tolerability as assessed by the Injection Site Grading scale will be 
summarized and plotted over time by category (pain, tenderness, erythema/redness, 
induration, and swelling) and severity using frequency counts and percentages. Local 
injection site tolerability will be assigned a severity grade, including none (grade 0), mild 
(grade 1), moderate (grade 2), severe (grade 3), or potentially life threatening (grade 4) 
utilizing the 5-point Injection Site Grading Scale. A listing will be provided. 
A separate listing will be presented for severe/life threatening responses with their 
corresponding VAS scores. 
12.4.4 
Injection Site Pain 
Injection Site Pain VAS scores will be summarized over time during the Treatment Period. 
And the maximum score during the Treatment Period will be calculated and tabulated. The 
burning/stinging categorical variable (Yes/No) will be summarized by percentage of 
responses in each dose received at each time point.   
The percentage of subjects who reported injection site reaction (Yes) at each injection visit 
in the Safety Analysis Set. Mean value of local injection site VAS pain scores will also be 
plotted at each injection.  
Separate listings for burning/stinging will be provided.  A listing of injection site pain VAS 
scores will also be provided. 
12.4.5 
Other Safety Variables 
NA. 
 
12.5 
INDEPENDENT DRUG COUNSELING/BEHAVIOURAL 
THERAPY 
A listing for whether independent drug counseling (IDC) was completed per subject visit 
will be provided. 


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13.0 
POOLED ANALYSES 
No pooled analyses will be conducted in this trial. 


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14.0 
SUBGROUP ANALYSES 
No subgroup analyses will be conducted in this trial. 
 
 


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15.0 
HEALTH OUTCOME ANALYSES 
No health outcome assessments were performed in this study. 


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16.0 
PLASMA CONCENTRATION ANALYSES 
No plasma concentration samples were collected in this study.  


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17.0 
INTERIM ANALYSIS 
No Interim analysis was performed for this study 


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18.0 
DETERMINATION OF SAMPLE SIZE 
This study is designed to provide ongoing treatment with RBP-6000 and to assess the 
safety monitoring for subjects who complete the RB-US-13-0003 study and for whom a 
new treatment venue has not been identified or arranged. Approximately 300 subjects 
who completed Study RB-US-13-0003 will be enrolled into this study. 
 


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19.0 
COMPUTER METHODS 
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Windows 
operating system. 


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20.0 
DATA HANDLING CONVENTIONS 
20.1 
REFERENCE DATES AND ANALYSIS PERIODS 
There are two analysis periods in this study:  
• Treatment Period (TP)  
• Safety Follow-Up Period (SFU).  
Treatment Period starts from Treatment Start Date and ends at Treatment End Date. 
Treatment Start Date (or Day 1) for a subject is the date of the first injection. Treatment 
End Date for a subject is the maximum of the date of the end-of-study/ Early Termination 
(EOS/ET) visit and the date of last injection + 28. 
Safety Follow-Up Period starts from Safety Follow-Up Start Date and ends at Safety 
Follow-Up End Date, which are defined for all subject who have assessments in the 
Follow-Up period. 
Safety Follow-Up Start Date for a subject is Treatment End Date +1. 
Safety Follow-Up End Date for a subject is defined as the date of visit at Week 29 or 
unscheduled visit after the Treatment End Date (defined as above) for AE/concomitant 
medication reporting or lab/vital signs assessment, whichever comes later. That is, Follow-
up end date is max (Follow-up Start Date, date of visit at Week 29, last unscheduled visit 
after the Treatment End Date to report AE/concomitant medication or to do lab/vital signs 
assessment, if available).  
Any records collected prior to first injection date/time will be considered as Screening 
records. And any records collected after the Treatment End Date will be considered as 
Safety Follow-up records.  
20.2 
ANALYSIS VISITS AND OTHER DEFINITIONS 
All data will be presented in listings (including unscheduled visits), however only per-
protocol visits will be summarized in tables and figures. Unscheduled and scheduled 
assessments will be utilized in the summaries for “at any time”.  
For lab values, body weight, BMI, waist circumference, hip circumference and waist-to-
hip ratio, Early Termination and End-of-study results will be reported with the EOS/ET 
visit. 
For all other assessments, occurring at the ET visit, will be mapped to the next per-
protocol visit (or time point), that has not already been completed by the subject. A ET 
visit must not be mapped to a visit that a subject has already completed.  


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The closest assessment value on or before Treatment Start Date/Time will be assigned as 
Baseline value and then be labeled as ‘Baseline’ in visit window, and for assessment prior 
to Treatment Start Date/Time, if exists, will be labeled as ‘EOS 0003’ or ‘Screening’ per 
its collecting time and per SOE definition.  
For subjects who have one visit-based assessment in the Safety Follow-up (SFU) period, 
the period of the visit will be labeled as ‘Safety Follow-Up Week 29’. 
 
Other Definitions: 
Subgroups 
Sex 
• Male 
• Female 
Age Categories 
• ≥ 18 to < 30 
• ≥ 30 to < 45 
• ≥ 45 to < 60 
• ≥ 60 
• ≥ 65 
Race 
• White 
• Non-White 
Baseline BMI Categories 
• Under weight: 0 to < 18.5 kg/m2 
• Normal: ≥ 18.5 kg/m2 and < 25 kg/m2 
• Over weight: ≥ 25 kg/m2 and < 30 kg/m2 
• Obese: ≥ 30 kg/m2 
 


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20.3 
DERIVED EFFICACY VARIABLES 
Not applicable. 
20.4 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS 
See reference rules on unscheduled assessments in Section 20.2. Unscheduled assessments 
will be utilized in analyses “at any time” and will be listed in listings.  
If there are more one assessments on one parameter at scheduled visits, the last assessment 
will be used for visit-based table/figure summaries. 
20.5 
MISSING DATE OF INVESTIGATIONAL PRODUCT 
When the date of the last injection of RBP-6000 during the Treatment Period is missing 
for a subject in the Safety Population, all efforts should be made to obtain the date from 
the investigator. If it is still missing after all efforts, then the last available dosing record 
date will be used as the last dose date.  
20.6 
MISSING SEVERITY AND RELATIONSHIP TO STUDY DRUG IN 
ADVERSE EVENTS 
If the severity is missing for an AE started on or after the date of the first dose of the 
investigational product, then a severity of “Severe” will be assigned.  
If the relationship is missing for an AE started on or after the date of the first dose of the 
investigational product, then a relationship of “Related” will be assigned.  
The imputed values for assessment will be used for incidence summary, while the actual 
values will be presented in data listings. 
20.7 
MISSING DATE INFORMATION FOR ADVERSE EVENTS 
When the AE start date is incomplete (i.e., partially missing), then the following rules will 
be applied: 
Missing day and month 
• If the year is the same as the year of the date of the first dose of investigational product, 
then the day and month of the date of the first dose of investigational product will be 
assigned to the missing fields. 
• If the year is before the year of the date of the first dose of investigational product, then 
December 31 will be assigned to the missing fields. 


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• If the year is after the year of the date of the first dose of investigational product, then 
January 1 will be assigned to the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
Missing day only  
• If the month and year are the same as the month and year of the date of the first dose 
of investigational product, then the day of the first dose of investigational product will 
be assigned to the missing day. 
• If either the year is before the year of the date of the first dose of investigational product 
or if both years are the same but the month is before the month of the date of the first 
dose of investigational product, then the last day of the month will be assigned to the 
missing day. 
• If either the year is after the year of the date of the first dose of investigational product 
or if both years are the same but the month is after the month of the date of the first 
dose of investigational product, then the first day of the month will be assigned to the 
missing day. 
If the stop date is after the date of the first dose of investigational product, the date of the 
first dose of investigational product will be assigned to the missing start date 
If the stop date is before the date of the first dose of investigational product, the stop date 
will be assigned to the missing start date 
20.8 
MISSING 
DATE 
INFORMATION 
FOR 
CONCOMITANT 
MEDICATIONS 
For concomitant medications, incomplete (i.e., partial missing) start date and/or stop date 
will be imputed. When the start date and the stop date are both incomplete for a subject, 
consider to impute the start date first. 
Missing day and month 
• If the year of the incomplete start date is the same as the year of the date of the first 
dose of investigational product, then the day and month of the date of the first dose will 
be assigned to the missing fields. 
• If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then January 1 will be assigned to the missing fields. 


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


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• If either the year is after the year of the date of the last dose of investigational product 
or if both years are the same but the month is after the month of the date of the last dose 
of investigational product, then the first day of the month will be assigned to the 
missing day. 
20.9 
CHARACTER 
VALUES 
OF 
CLINICAL 
LABORATORY 
PARAMETERS AND OTHER LABORATORY IMPUTATION 
RULES 
• If a reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table due, for example, to the fact that a character string is reported for a 
parameter of the numerical type, a coded value needs to be appropriately determined 
and used in the statistical analyses. Value of X+0.0001 will be used to impute “>X” 
character value and X-0.0001 will be used to impute “<X”. That is, if X equal to 60, 
60.0001 will be used to impute character value of “>60” and 59.999 will be used to 
impute “<60”. However, the actual values as reported in the database may be presented 
in data listings. 
• Due to the fact that screening lab records were rolled-over from RB-US-13-0003, 
whose LDH, total bilirubin and AST records have lower limits and HDL-C records 
have upper limit as opposed to at visits after first injection only having one-sided 
upper limits for parameters LDH, total bilirubin  and AST and one-sided lower limit 
for HDL-C, lab classsification values (i.e., Low, normal and high) for parameters 
LDH, total bilirubin  and AST and HDL-C at screening and from RB-US-13-0003 
should be imputed so that shift tables can be tabulated. The imputation rules are as 
follows:  
o For screening records (ie, rolled-over from RB-US-13-0003) of parameters 
LDH, total bilirubin  and AST, lower limits will be imputed as 0. The lab 
character values of “Low” and “Normal” will be collapsed to be “Normal”.     
o For screening records (ie, rolled-over from RB-US-13-0003) of HDL-C, upper 
limit will be imputed as blank. The lab character values of “Normal” and 
“High” will be collapsed to be “Normal”.     
• GGT assessments at Screening have categories of normal and high but have three 
categories of low, normal and high post-baseline. Then for GGT post-baseline 
assessments, low and normal will be collapsed to normal.     
20.10 
C-SSRS DATA IMPUTATION 
In the Suicidal Behavior section, when the answer to the question “Have you made a 
suicide attemp” is NO, then the “Total # of Attempts” should be 0. In our clincial 
database, we have both 0 and Blank present. In the analysis dataset, under this scenario, 
Blank for Total # of Attempts will be imputed as 0.   


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21.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
No changes have been made to analyses specified in protocol.  


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22.0 
REFERENCES 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation:  
U.S. Department of Health and Human Services Food and Drug Administration Center 
for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and 
Research (CBER) 


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23.0 
APPENDIX 
23.1 
APPENDIX 1: LIST OF PREFERRED TERMS FROM STANDARD 
MEDDRA QUERIES FOR ADVERSE EVENTS OF SPECIAL 
INTEREST 
 LIST OF PREFERRED TERMS FOR PSYCHIATRIC HISTORY 
Adjustment disorder with anxiety 
Cyclothymic disorder 
Adjustment disorder with depressed mood Bipolar disorder 
Adjustment disorder with disturbance of 
conduct 
Hypomania 
Adjustment disorder with mixed anxiety 
and depressed mood 
Mania 
Adjustment disorder with mixed 
disturbance of emotion and conduct 
Blunted affect 
Grief reaction 
Constricted affect 
Adjustment disorder 
Flat affect 
Agitation 
Inappropriate affect 
Agitation neonatal 
Affect lability 
Anticipatory anxiety 
Affective ambivalence 
Anxiety 
Anger 
Nervousness 
Dysphoria 
Stress 
Emotional disorder 
Tension 
Emotional poverty 
Activation syndrome 
Euphoric mood 
Acute stress disorder 
Irritability 
Post-traumatic stress disorder 
Moaning 
Postpartum stress disorder 
Mood altered 
Burnout syndrome 
Emotional distress 
Anniversary reaction 
Neuroleptic-induced deficit syndrome 
Acrophobia 
Alexithymia 
Agoraphobia 
Frustration tolerance decreased 
Animal phobia 
Mood swings 
Claustrophobia 
Affective disorder 
Fear 
Apathy 
Fear of animals 
Listless 
Fear of closed spaces 
Mood disorder due to a general medical condition 
Fear of disease 
Seasonal affective disorder 
Fear of open spaces 
Boredom 


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Fear of weight gain 
Laziness 
Performance fear 
Substance-induced mood disorder 
Phobia 
Aggression 
Phobia of exams 
Antisocial behaviour 
Phobia of flying 
Asocial behaviour 
Phobic avoidance 
Attention-seeking behaviour 
Social anxiety disorder 
Belligerence 
Social fear 
Disinhibition 
Fear of falling 
Grandiosity 
Dysmorphophobia 
Hostility 
Ochlophobia 
Indifference 
Phagophobia 
Inferiority complex 
Fear of crowded places 
Negativism 
Fear of eating 
Paranoia 
Arachnophobia 
Personality change 
Hydrophobia 
Social avoidant behaviour 
Phonophobia 
Soliloquy 
Phobia of driving 
Suspiciousness 
Noctiphobia 
Violence-related symptom 
Nocturnal fear 
Homicidal ideation 
Osmophobia 
Impatience 
Nosophobia 
Disturbance in social behaviour 
Photaugiaphobia 
Aversion 
Thanatophobia 
Suggestibility 
Fear of death 
Stubbornness 
Fear of pregnancy 
Pseudologia 
Haphephobia 
Overconfidence 
Paruresis 
Egocentrism 
Pharmacophobia 
Defiant behaviour 
Emetophobia 
Personality disorder 
Autophobia 
Pithiatism 
Haemophobia 
Self esteem decreased 
Fear of injection 
Self esteem inflated 
Thermophobia 
Avoidant personality disorder 
Algophobia 
Dependent personality disorder 
Limited symptom panic attack 
Obsessive-compulsive personality disorder 
Panic attack 
Antisocial personality disorder 
Panic disorder 
Borderline personality disorder 
Panic reaction 
Histrionic personality disorder 


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Compulsions 
Narcissistic personality disorder 
Obsessive thoughts 
Psychopathic personality 
Obsessive-compulsive disorder 
Paranoid personality disorder 
Trichotillomania 
Schizoid personality disorder 
Body dysmorphic disorder 
Schizotypal personality disorder 
Obsessive rumination 
Breath holding 
Dermatillomania 
Staring 
Compulsive lip biting 
Regressive behaviour 
Nail picking 
Abnormal behaviour 
Compulsive shopping 
Sexually inappropriate behaviour 
Compulsive hoarding 
Behaviour disorder due to a general medical condition 
Compulsive handwashing 
Scatolia 
Paediatric autoimmune neuropsychiatric 
disorders associated with streptococcal 
infection 
Neglect of personal appearance 
Trichotemnomania 
Trance 
Compulsive cheek biting 
Hypervigilance 
Obsessive need for symmetry 
Abulia 
Obsessive-compulsive symptom 
Psychiatric symptom 
Anxiety disorder due to a general medical 
condition 
Psychiatric decompensation 
Generalised anxiety disorder 
Decreased eye contact 
Neurosis 
Psychological trauma 
Postpartum neurosis 
Helplessness 
Selective mutism 
Personality change due to a general medical condition 
Separation anxiety disorder 
Mental disorder due to a general medical condition 
Anxiety disorder 
Neuropsychiatric syndrome 
Catatonia 
Psychological factor affecting medical condition 
Restlessness 
Mental status changes 
Automatism 
Dyslogia 
Automatism epileptic 
Mental disorder 
Automatism, command 
Emotional disorder of childhood 
Bruxism 
Neurotic disorder of childhood 
Echolalia 
Personality disorder of childhood 
Echopraxia 
Reactive attachment disorder of infancy or early 
childhood 
Head banging 
School refusal 
Posturing 
Disinhibited social engagement disorder of childhood 
Stereotypy 
Encopresis 
Waxy flexibility 
Enuresis 


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Tic 
Alcohol abuse 
Chronic tic disorder 
Alcohol problem 
Complex tic 
Alcoholic hangover 
Provisional tic disorder 
Alcoholism 
Secondary tic 
Dependence 
Attention deficit/hyperactivity disorder 
Drug abuse 
Atypical attention deficit syndrome 
Drug dependence 
Oppositional defiant disorder 
Drug dependence, antepartum 
Conduct disorder 
Drug dependence, postpartum 
Disruptive mood dysregulation disorder 
Tobacco abuse 
Change in sustained attention 
Withdrawal syndrome 
Distractibility 
Alcohol withdrawal syndrome 
Daydreaming 
Nicotine dependence 
Executive dysfunction 
Tobacco withdrawal symptoms 
Vascular cognitive impairment 
Neonatal complications of substance abuse 
Mental fatigue 
Substance abuse 
Learning disability 
Dopamine dysregulation syndrome 
Reading disorder 
Binge drinking 
Learning disorder 
Substance dependence 
Mutism 
Gambling disorder 
Communication disorder 
Brief psychotic disorder, with postpartum onset 
Speech sound disorder 
Brief psychotic disorder with marked stressors 
Clang associations 
Transient psychosis 
Logorrhoea 
Brief psychotic disorder without marked stressors 
Neologism 
Alice in wonderland syndrome 
Verbigeration 
Delusional disorder, erotomanic type 
Taciturnity 
Delusional disorder, grandiose type 
Disorganised speech 
Delusional disorder, jealous type 
Coprolalia 
Delusional disorder, mixed type 
Lack of spontaneous speech 
Delusional disorder, somatic type 
Poverty of speech 
Delusional disorder, unspecified type 
Pressure of speech 
Delusional disorder, persecutory type 
Screaming 
Acute psychosis 
Dysphemia 
Alcoholic psychosis 
Confusional state 
Psychotic behaviour 
Disorientation 
Senile psychosis 
Delirium 
Shared psychotic disorder 
Delirium tremens 
Reactive psychosis 
Delirium febrile 
Epileptic psychosis 


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Post-traumatic amnestic disorder 
Childhood psychosis 
Korsakoff's syndrome 
Psychotic disorder 
Paramnesia 
Psychotic disorder due to a general medical condition 
Pseudodementia 
Hysterical psychosis 
Behavioural and psychiatric symptoms of 
dementia 
Postictal psychosis 
Agitated depression 
Substance-induced psychotic disorder 
Depression 
Rebound psychosis 
Depression suicidal 
Parkinson's disease psychosis 
Postpartum depression 
Schizoaffective disorder 
Major depression 
Schizophreniform disorder 
Menopausal depression 
Schizoaffective disorder bipolar type 
Childhood depression 
Schizoaffective disorder depressive type 
Post stroke depression 
Schizophrenia 
Postictal depression 
Anorgasmia 
Persistent depressive disorder 
Female orgasmic disorder 
Anhedonia 
Male orgasmic disorder 
Decreased interest 
Orgasm abnormal 
Depressed mood 
Premature ejaculation 
Feeling of despair 
Orgasmic sensation decreased 
Feelings of worthlessness 
Psychosexual disorder 
Morose 
Sex dysphoria 
Psychomotor retardation 
Sexual inhibition 
Tearfulness 
Psychogenic erectile dysfunction 
Feeling guilty 
Disturbance in sexual arousal 
Depressive symptom 
Excessive masturbation 
Negative thoughts 
Libido decreased 
Sense of a foreshortened future 
Libido increased 
Autism spectrum disorder 
Loss of libido 
Neurodevelopmental disorder 
Sexual aversion disorder 
Dissociation 
Excessive sexual fantasies 
Dissociative amnesia 
Libido disorder 
Dissociative disorder 
Hypersexuality 
Dissociative identity disorder 
Compulsive sexual behaviour 
Depersonalisation/derealisation disorder 
Genito-pelvic pain/penetration disorder 
Delusion 
Exhibitionism 
Delusion of grandeur 
Fetishism 
Delusion of reference 
Frotteurism 
Delusion of replacement 
Masochism 


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Erotomanic delusion 
Paedophilia 
Jealous delusion 
Paraphilia 
Persecutory delusion 
Sadism 
Somatic delusion 
Transvestism 
Thought insertion 
Voyeurism 
Thought withdrawal 
Initial insomnia 
Thought broadcasting 
Insomnia 
Cotard's syndrome 
Middle insomnia 
Depressive delusion 
Hyposomnia 
Mixed delusion 
Terminal insomnia 
Deja vu 
Behavioural insomnia of childhood 
Delusional perception 
Breathing-related sleep disorder 
Derealisation 
Dyssomnia 
Flashback 
Hypnagogic hallucination 
Hallucination 
Hypnopompic hallucination 
Hallucination, auditory 
Sleep attacks 
Hallucination, gustatory 
Abnormal dreams 
Hallucination, olfactory 
Nightmare 
Hallucination, tactile 
Rapid eye movements sleep abnormal 
Hallucination, visual 
Sleep talking 
Hallucinations, mixed 
Sleep terror 
Illusion 
Somnambulism 
Jamais vu 
Abnormal sleep-related event 
Somatic hallucination 
Parasomnia 
Hallucination, synaesthetic 
Loss of dreaming 
Paroxysmal perceptual alteration 
Sleep-related eating disorder 
Time perception altered 
Sleep sex 
Autoscopy 
Sleep inertia 
Circumstantiality 
Confusional arousal 
Confabulation 
Rapid eye movement sleep behaviour disorder 
Derailment 
Sleep disorder due to general medical condition, 
hypersomnia type 
Flight of ideas 
Sleep disorder due to general medical condition, 
insomnia type 
Ideas of reference 
Sleep disorder due to general medical condition, mixed 
type 
Illogical thinking 
Sleep disorder due to general medical condition, 
parasomnia type 
Loose associations 
Sleep disorder due to a general medical condition 
Magical thinking 
Sleep disorder 


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Perseveration 
Hypersomnia-bulimia syndrome 
Poverty of thought content 
Sopor 
Tangentiality 
Hypersomnia related to another mental condition 
Thinking abnormal 
Insomnia related to another mental condition 
Thought blocking 
Completed suicide 
Bradyphrenia 
Intentional self-injury 
Morbid thoughts 
Suicidal ideation 
Intellectualisation 
Suicide attempt 
Tachyphrenia 
Self-injurious ideation 
Impaired reasoning 
Self injurious behaviour 
Paralogism 
Suicidal behaviour 
Pathological doubt 
Suicide threat 
Intrusive thoughts 
Compensation neurosis 
Purging 
Munchausen's syndrome 
Self-induced vomiting 
Factitious disorder 
Eating disorder symptom 
Conversion disorder 
Anorexia and bulimia syndrome 
Polydipsia psychogenic 
Anorexia nervosa 
Psychogenic dysuria 
Binge eating 
Torticollis psychogenic 
Bulimia nervosa 
Vomiting psychogenic 
Eating disorder 
Psychosomatic disease 
Merycism 
Pseudoneurologic symptom 
Pica 
Psychogenic seizure 
Food aversion 
Psychogenic movement disorder 
Selective eating disorder 
Psychogenic tremor 
Impulsive behaviour 
Psychogenic respiratory distress 
Intermittent explosive disorder 
Somatoform genitourinary disorder 
Kleptomania 
Somatic symptom disorder 
Poriomania 
Illness anxiety disorder 
Pyromania 
Cardiovascular somatic symptom disorder 
Onychophagia 
Gastrointestinal somatic symptom disorder 
Impulse-control disorder 
Neurologic somatic symptom disorder 
Necromania 
Cutaneous somatic symptom disorder 
Clinomania 
Somatic symptom disorder of pregnancy 
Bipolar I disorder 
 
Bipolar II disorder 
 


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CUSTOMIZED MEDDRA QUERY (CMQ) LIST OF PREFERRED TERMS FOR 
DRUG RELATED HEPATIC DISORDERS 
Cholestasis and jaundice of hepatic origin 
Bilirubin excretion disorder 
Jaundice 
Cholaemia 
Jaundice cholestatic 
Cholestasis 
Jaundice hepatocellular 
Cholestatic liver injury 
Mixed liver injury 
Cholestatic pruritus 
Ocular icterus 
Drug-induced liver injury 
Parenteral nutrition associated liver disease 
Hepatitis cholestatic 
Deficiency of bile secretion 
Hyperbilirubinaemia 
Yellow skin 
Icterus index increased 
 
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions 
Acute hepatic failure 
Liver and small intestine transplant 
Acute on chronic liver failure 
Liver dialysis 
Acute yellow liver atrophy 
Liver disorder 
Ascites 
Liver injury 
Asterixis 
Liver operation 
Bacterascites 
Liver transplant 
Biliary cirrhosis 
Lupoid hepatic cirrhosis 
Biliary cirrhosis primary 
Minimal hepatic encephalopathy 
Biliary fibrosis 
Mixed liver injury 
Cholestatic liver injury 
Nodular regenerative hyperplasia 
Chronic hepatic failure 
Non-alcoholic fatty liver 
Coma hepatic 
Non-alcoholic steatohepatitis 
Cryptogenic cirrhosis 
Non-cirrhotic portal hypertension 
Diabetic hepatopathy 
Oedema due to hepatic disease 
Drug-induced liver injury 
Oesophageal varices haemorrhage 
Duodenal varices 
Peripancreatic varices 
Gallbladder varices 
Portal fibrosis 
Gastric variceal injection 
Portal hypertension 
Gastric variceal ligation 
Portal hypertensive enteropathy 
Gastric varices 
Portal hypertensive gastropathy 
Gastric varices haemorrhage 
Portal vein cavernous transformation 


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Hepatectomy 
Portal vein dilatation 
Hepatic atrophy 
Porto pulmonary hypertension 
Hepatic calcification 
Renal and liver transplant 
Hepatic cirrhosis 
Retrograde portal vein flow 
Hepatic encephalopathy 
Reye's syndrome 
Hepatic encephalopathy prophylaxis 
Reynold's syndrome 
Hepatic failure 
Splenic varices 
Hepatic fibrosis 
Splenic varices haemorrhage 
Hepatic hydrothorax 
Steatohepatitis 
Hepatic infiltration eosinophilic 
Subacute hepatic failure 
Hepatic lesion 
Varices oesophageal 
Hepatic necrosis 
Varicose veins of abdominal wall 
Hepatic steato-fibrosis 
Anorectal varices 
Hepatic steatosis 
Anorectal varices haemorrhage 
Hepatitis fulminant 
Intrahepatic portal hepatic venous fistula 
Hepatobiliary disease 
Peritoneovenous shunt 
Hepatocellular foamy cell syndrome 
Portal shunt 
Hepatocellular injury 
Portal shunt procedure 
Hepatopulmonary syndrome 
Small-for-size liver syndrome 
Hepatorenal failure 
Spider naevus 
Hepatorenal syndrome 
Splenorenal shunt 
Hepatotoxicity 
Splenorenal shunt procedure 
Intestinal varices 
Spontaneous intrahepatic portosystemic venous shunt 
Intestinal varices haemorrhage 
Stomal varices 
Varicose vein 
Hepatitis, non-infectious 
Acute graft versus host disease in liver 
Hepatitis fulminant 
Allergic hepatitis 
Hepatitis toxic 
Autoimmune hepatitis 
Ischaemic hepatitis 
Chronic graft versus host disease in liver 
Lupus hepatitis 
Chronic hepatitis 
Non-alcoholic steatohepatitis 
Graft versus host disease in liver 
Radiation hepatitis 
Hepatitis 
Steatohepatitis 
Hepatitis acute 
Granulomatous liver disease 
Hepatitis cholestatic 
Liver sarcoidosis 
Hepatitis chronic active 
Portal tract inflammation 


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Hepatitis chronic persistent 
Liver related investigations, signs and symptoms 
Alanine aminotransferase abnormal 
Hypercholia 
Alanine aminotransferase increased 
Hypertransaminasaemia 
Ammonia abnormal 
Kayser-Fleischer ring 
Ammonia increased 
Liver function test abnormal 
Ascites 
Liver induration 
Aspartate aminotransferase abnormal 
Liver palpable 
Aspartate aminotransferase increased 
Liver scan abnormal 
Bacterascites 
Liver tenderness 
Bile output abnormal 
Mitochondrial aspartate aminotransferase increased 
Bile output decreased 
Molar ratio of total branched-chain amino acid to tyrosine 
Biliary ascites 
Oedema due to hepatic disease 
Bilirubin conjugated abnormal 
Perihepatic discomfort 
Bilirubin conjugated increased 
Retrograde portal vein flow 
Bilirubin urine present 
Total bile acids increased 
Biopsy liver abnormal 
Transaminases abnormal 
Blood bilirubin abnormal 
Transaminases increased 
Blood bilirubin increased 
Ultrasound liver abnormal 
Blood bilirubin unconjugated increased 
Urine bilirubin increased 
Bromosulphthalein test abnormal 
X-ray hepatobiliary abnormal 
Child-Pugh-Turcotte score abnormal 
5'nucleotidase increased 
Child-Pugh-Turcotte score increased 
Blood alkaline phosphatase abnormal 
Computerised tomogram liver 
Blood alkaline phosphatase increased 
Foetor hepaticus 
Blood cholinesterase abnormal 
Galactose elimination capacity test 
abnormal 
Blood cholinesterase decreased 
Galactose elimination capacity test 
decreased 
Deficiency of bile secretion 
Gamma-glutamyltransferase abnormal 
Glutamate dehydrogenase increased 
Gamma-glutamyltransferase increased 
Haemorrhagic ascites 
Guanase increased 
Hepatic fibrosis marker abnormal 
Hepaplastin abnormal 
Hepatic fibrosis marker increased 
Hepaplastin decreased 
Hypoalbuminaemia 
Hepatic artery flow decreased 
Leucine aminopeptidase increased 
Hepatic congestion 
Liver function test decreased 
Hepatic enzyme abnormal 
Liver function test increased 


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Hepatic enzyme decreased 
Liver iron concentration abnormal 
Hepatic enzyme increased 
Liver iron concentration increased 
Hepatic function abnormal 
Model for end stage liver disease score abnormal 
Hepatic hydrothorax 
Model for end stage liver disease score increased 
Hepatic hypertrophy 
Periportal oedema 
Hepatic mass 
Peritoneal fluid protein abnormal 
Hepatic pain 
Peritoneal fluid protein decreased 
Hepatic sequestration 
Peritoneal fluid protein increased 
Hepatic vascular resistance increased 
Pneumobilia 
Hepatobiliary scan abnormal 
Portal vein flow decreased 
Hepatomegaly 
Portal vein pressure increased 
Hepatosplenomegaly 
Retinol binding protein decreased 
Hyperammonaemia 
Urobilinogen urine decreased 
Hyperbilirubinaemia 
Urobilinogen urine increased 
Hepatic disorders specifically reported as alcohol-related 
Alcoholic liver disease 
Hepatic steato-fibrosis 
Cirrhosis alcoholic 
Hepatitis alcoholic 
Fatty liver alcoholic 
Zieve syndrome 
 
CMQ LIST OF PREFERRED TERMS FOR INJECTION SITE REACTION 
Immediate post-injection reaction 
Injection site ulcer 
Injection related reaction 
Injection site urticaria 
Injection site abscess 
Injection site vesicles 
Injection site cellulitis 
Injection site warmth 
Injection site infection 
Injection site ischaemia 
Injection site pustule 
Injection site coldness 
Injection site abscess sterile 
Injection site discolouration 
Injection site anaesthesia 
Injection site photosensitivity reaction 
Injection site atrophy 
Injection site swelling 
Injection site bruising 
Injection site discomfort 
Injection site cyst 
Injection site calcification 
Injection site dermatitis 
Injection site movement impairment 
Injection site erosion 
Injection site lymphadenopathy 
Injection site erythema 
Injection site nodule 
Injection site extravasation 
Embolia cutis medicamentosa 


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Injection site fibrosis 
Injection site scar 
Injection site granuloma 
Injection site discharge 
Injection site haematoma 
Injection site pallor 
Injection site haemorrhage 
Injection site papule 
Injection site hypersensitivity 
Injection site injury 
Injection site hypertrophy 
Injection site scab 
Injection site induration 
Injection site eczema 
Injection site inflammation 
Injection site streaking 
Injection site irritation 
Injection site dryness 
Injection site mass 
Injection site laceration 
Injection site necrosis 
Injection site macule 
Injection site nerve damage 
Injection site vasculitis 
Injection site oedema 
Injection site exfoliation 
Injection site pain 
Injection site dysaesthesia 
Injection site paraesthesia 
Injection site plaque 
Injection site phlebitis 
Injection site hyperaesthesia 
Injection site pruritus 
Injection site hypoaesthesia 
Injection site rash 
Injection site hypertrichosis 
Injection site reaction 
Injection site thrombosis 
 
CMQ LIST OF PREFERRED TERMS FOR CNS DEPRESSION 
Mental fatigue 
Hyporesponsive to stimuli 
Microsleep 
Benign familial neonatal convulsions 
Narcolepsy 
Febrile convulsion 
Coma 
Drug withdrawal convulsions 
Impaired driving ability 
Convulsion neonatal 
Impaired ability to use machinery 
Convulsions local 
Accident 
Tonic convulsion 
Road traffic accident 
Convulsion in childhood 
Vision blurred 
Clonic convulsion 
Vertigo CNS origin 
Acute encephalitis with refractory, repetitive partial 
seizures 
Incoherent 
Generalised tonic-clonic seizure 
Disturbance in attention 
Complex partial seizures 


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Judgement impaired 
Psychomotor seizures 
Mental impairment 
Simple partial seizures 
Borderline mental impairment 
Autonomic seizure 
Cognitive disorder 
Atonic seizures 
Altered state of consciousness 
Seizure 
Depressed level of consciousness 
Partial seizures with secondary generalisation 
Lethargy 
Alcoholic seizure 
Loss of consciousness 
Partial seizures 
Sedation 
Seizure like phenomena 
Somnolence 
Seizure cluster 
Somnolence neonatal 
Change in seizure presentation 
Stupor 
Migraine-triggered seizure 
Syncope 
Psychogenic seizure 
Postictal state 
Seizure anoxic 
Consciousness fluctuating 
Post stroke seizure 
Neonatal oversedation 
Accidental death 
Hypoglycaemic unconsciousness 
Accidental overdose 
Hyperglycaemic unconsciousness 
Accidental exposure to product 
Post-injection delirium sedation 
syndrome 
Cerebrovascular accident 
Preictal state 
Dizziness 
Psychogenic pseudosyncope 
Dizziness exertional 
Mental status changes 
Dizziness postural 
Mental status changes postoperative 
Procedural dizziness 
Slow response to stimuli 
Neurotoxicity 
Unresponsive to stimuli 
 
CMQ LIST OF PREFERRED TERMS FOR RESPIRATORY 
DEPRESSION/RESPIRATORY FAILURE 
Acute respiratory distress syndrome 
Neonatal respiratory arrest 
Acute respiratory failure 
Neonatal respiratory depression 
Apnoea 
Neonatal respiratory distress syndrome 
Apnoea neonatal 
Neonatal respiratory failure 
Infantile apnoea 
Respiratory arrest 
Apnoeic attack 
Respiratory depression 
Bradypnoea 
Respiratory depth decreased 


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Breath sounds absent 
Respiratory distress 
Cardio-respiratory distress 
Respiratory failure 
Central-alveolar hypoventilation 
Respiratory paralysis 
Chronic respiratory failure 
Respiratory rate decreased 
Hypopnoea 
Severe acute respiratory syndrome 
Hypoventilation 
Cardio-respiratory arrest 
Hypoventilation neonatal 
Cardio-respiratory arrest neonatal 
Lung hypoinflation 
Cardiopulmonary failure 
Meconium aspiration syndrome 
 
CMQ LIST OF PREFERRED TERMS FOR ORTHOSTATIC HYPOTENSION 
Orthostatic hypotension 
Syncope 
Vision blurred 
Presyncope 
Dizziness 
Diastolic hypotension 
Dizziness exertional 
Hypotension 
Dizziness postural 
 
CMQ LIST OF PREFERRED TERMS FOR WITHDRAWAL SYMPTOMS 
Agitation 
Malaise 
Anxiety 
Muscle spasms 
Arthralgia 
Muscle twitching 
Bone pain 
Myalgia 
Chills 
Mydriasis 
Decreased appetite 
Nausea 
Depression 
Piloerection 
Diarrhoea 
Pruritus 
Dizziness 
Psychomotor hyperactivity 
Drug dependence 
Pyrexia  
Flushing 
Respiratory rate increased 
Heart rate increased 
Restlessness 
Hyperhidrosis 
Rhinitis 
Hypertension 
Rhinorrhoea 
Hypervigilance 
Sneezing 
Influenza like illness 
Tachycardia 


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Insomnia 
Tremor 
Irritability 
Vomiting 
Lacrimal disorder 
Yawning 
Lacrimation increased 
Drug withdrawal symptoms 
Muscle strain 
 
CMQ LIST OF PREFERRED TERMS FOR ACUTE PANCREATITIS 
Amylase abnormal 
Oedematous pancreatitis 
Amylase creatinine clearance ratio 
abnormal 
Pancreatic abscess 
Amylase increased 
Pancreatic enzyme abnormality 
Bilirubin conjugated abnormal 
Pancreatic enzymes abnormal 
Blood bilirubin increased 
Pancreatic enzymes increased 
Blood trypsin increased 
Pancreatic haemorrhage 
Cullen's sign 
Pancreatic necrosis 
Grey Turner's sign 
Pancreatic phlegmon 
Haemorrhagic necrotic pancreatitis 
Pancreatic pseudocyst 
Hereditary pancreatitis 
Pancreatic pseudocyst drainage 
Hyperamylasaemia 
Pancreatitis 
Hyperbilirubinaemia 
Pancreatitis acute 
Hyperlipasaemia 
Pancreatitis haemorrhagic 
Ischaemic pancreatitis 
Pancreatitis necrotising 
Lipase abnormal 
Pancreatitis relapsing 
Lipase increased 
Pancreatorenal syndrome 
Lipase urine increased 
 
23.2 
APPENDIX 2: LIST OF CYP3A4 INHIBITOR MEDICATIONS 
Generic/Brand Name 
Category 
Generic/Brand Name 
Category 
Alprazolam 
weak 
isoniazid 
weak 
Amiodarone 
weak 
istradefylline 
weak 
Amlodipine 
weak 
Itraconazole 
strong 
Amprenavir 
moderate 
ivacaftor 
weak 
Aprepitant 
moderate 
Ketoconazole 
strong 
Atazanavir 
moderate 
lapatinib 
weak 
Atorvastatin 
weak 
lomitapide 
weak 
Bicalutamide 
weak 
lopinavir 
strong 


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boceprevir 
strong 
Mestranol 
weak 
Chloramphenicol 
unclassified 
Metronidazole 
unclassified 
chlorzoxazone 
weak 
Mibefradil 
strong 
cilostazol 
weak 
Miconazole 
unclassified 
Cimetidine 
moderate 
Mifepristone 
unclassified 
Ciprofloxacin 
moderate 
Nefazodone 
 strong 
Clarithromycin 
strong 
Nelfinavir 
 strong 
Clotrimazole 
moderate 
Nicardipine 
unclassified 
cobicistat 
 strong 
nilotinib 
weak 
conivaptan 
 strong 
Norfloxacin 
unclassified 
crizotinib 
moderate 
Norfluoxetine 
unclassified 
Cyclosporine 
moderate 
ombitasvir  
 strong 
danoprevir  
strong 
paritaprevir  
 strong 
darunavir 
moderate 
pazopanib 
weak 
dasabuvir 
 strong 
posaconazole 
strong 
Delavirdine 
 strong 
Progestogen 
weak 
Diethyldithiocarbamate 
unclassified 
Propofol 
unclassified 
Diltiazem 
strong 
Quinine 
unclassified 
dronedarone 
moderate 
Ranitidine 
weak 
elvitegravir  
strong 
ranolazine 
weak 
Erythromycin 
moderate 
Ritonavir 
 strong 
estradiol  
weak 
Saquinavir 
 strong 
ethinyl 
weak 
Sertraline 
unclassified 
Fluconazole 
moderate 
Starfruit 
unclassified 
Fluoxetine 
weak 
tacrolimus 
weak 
Fluvoxamine 
moderate 
Telaprevir 
 strong 
fosamprenavir 
moderate 
Telithromycin 
 strong 
fosaprepitant 
weak 
ticagrelor 
weak 
Gestodene 
weak 
tipranavir   
strong 
ginkgo 
weak 
tofisopam 
moderate 
goldenseal 
weak 
troleandomycin 
strong 
grapefruit 
 strong 
Verapamil 
moderate 
idelalisib 
 strong 
voriconazole 
strong 
 
 
 
 
 


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23.3 
APPENDIX 3: TABLES, FIGURES AND LISTINGS  
 
Tables 
 
14.1 Demographic Data Tables & Figures 
Table 14.1.1.1 Subject Disposition – All Screened Subjects 
Table 14.1.1.2 Enrollment by Site – All Screened Subjects 
Table 14.1.1.3 Enrollment by Site - Safety Analysis Set 
Table 14.1.1.4 Subject Analysis Sets - All Screened Subjects 
Table 14.1.2.1 Demographic and Baseline Characteristics – Safety Analysis Set 
Table 14.1.3.1 Medical History - Safety Analysis Set 
Table 14.1.4.1 Substance Use – Safety Analysis Set 
Table 14.1.5.1 Summary of Prior Medications – Safety Analysis Set 
Table 14.1.5.2 Summary of Concomitant Medications during RBP-6000 Dosing – Safety Analysis Set 
Table 14.1.5.3 Summary of Concomitant Medications post RBP-6000 Dosing– Safety Analysis Set 
Table 14.1.5.4 Summary of Subjects Who have taken CNS Depressant Medications during RBP-6000 Dosing (using 
Concomitant medication data and Urine Drug Screening)– Safety Analysis Set 
Table 14.1.5.5 Summary of CNS Depressant Medications Taken during RBP-6000 dosing – Safety Analysis Set 
Table 14.1.5.6 Summary of CYP3A4 Inhibitor Medications by Category (Unclassified, Weak, Moderate or Strong 
inhibitors) during RBP-6000 dosing – Safety Analysis Set 
Table 14.1.5.7 Summary of CYP3A4 Inhibitor Medications by Category (Unclassified, Weak, Moderate or Strong 
inhibitors) post RBP-6000 dosing – Safety Analysis Set 
Table 14.1.6.1 Summary of RBP-6000 Exposure – Safety Analysis Set  
Table 14.1.6.2 Cumulative Frequency Distribution of RBP-6000 Exposure – Safety Analysis Set 
 
Table 14.1.6.3 Summary of RBP-6000 Injections – Safety Analysis Set  
Table 14.1.6.4 Cumulative Frequency Distribution of RBP-6000 Injections – Safety Analysis Set 
 
Table 14.1.6.5 Dose Level Over Time During the Treatment Period – Safety Analysis Set  
Table 14.1.6.6 Dose Level Over Time During the Treatment Period for Subjects Who Received 100 mg at the First 
Injection – Safety Analysis Set 
 
Table 14.1.6.7 Dose Level Over Time During the Treatment Period for Subjects Who Received 300 mg at the First 
Injection – Safety Analysis Set 
 
Table 14.1.6.8 Dose Modification and its Reason Over Time During the Treatment Period – Safety Analysis Set 
 
Figure 14.1.6.8 Stacked Bar Chart of Dose Modification Over Time During the Treatment Period – Safety Analysis Set  
Table 14.1.6.9 Frequency Distribution of Total Number of Injections in the Treatment Period by Dose Level – Safety 
Analysis Set 
 
Table 14.1.6.10 Frequency Distribution of Days Since Last Injection During the Treatment Period – Safety Analysis Set  
Figure 14.1.6.10 Distribution of Actual Injection Days Over Time During the Treatment Period – Safety Analysis Set 
 
14.2 Efficacy Data Tables 
 
Table 14.2.1.1 Cumulative Distribution Function of the Percentage of Urine Samples Negative for Opioids in the 
treatment period – Safety Analysis Set  
Table 14.2.1.2 Number and Percentage of Subjects with Urine Samples Negative for Opioids by Visit – Safety Analysis 
Set 
 
Table 14.2.1.3 Urine Toxicology for Drug Usage for All Visits in the Treatment Period – Safety Analysis Set 
 
14.3 Safety Data Tables & Figures 
 
Table 14.3.1.1 Overall Summary of Treatment-Emergent Adverse Events – Safety Analysis Set 
 
Table 14.3.1.2 Summary of Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term 
During the Treatment Period – Safety Analysis Set  
Table 14.3.1.3 Summary of Treatment-Emergent Adverse Events Experienced by >=5% of Subjects by MedDRA 
Preferred Term During Treatment Period– Safety Analysis Set  


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Table 14.3.14 Summary of Treatment-Emergent Adverse Events Leading to Discontinuation by MedDRA System Organ 
Class and Preferred Term During Treatment Period- Safety Analysis Set 
 
Table 14.3.1.5 Summary of Deaths due to Adverse Event (AE) - Safety Analysis Set 
 
Table 14.3.1.6 Summary of Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term During Treatment Period– Safety Analysis Set 
 
Table 14.3.1.7 Summary of Serious Treatment-Emergent Adverse Events Related to Study Treatment by MedDRA 
System Organ Class and Preferred Term During Treatment Period– Safety Analysis Set 
 
Table 14.3.1.8 Summary of Treatment-Emergent Adverse Events by Maximum Severity, MedDRA System Organ Class 
and Preferred Term During Treatment Period – Safety Analysis Set 
 
Table 14.3.1.9 Summary of Treatment-Emergent Adverse Events Related to Study Treatment by Maximum Severity, 
MedDRA System Organ Class and Preferred Term During the Treatment Period- Safety Analysis Set 
Table 14.3.1.10 Summary of Severe Treatment-Emergent Adverse Events Related to Study Treatment Leading to 
Discontinuation by MedDRA System Organ Class and Preferred Term During the Treatment Period- Safety Analysis Set  
Table 14.3.1.11 Summary of Severe Treatment-Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term During the Treatment Period- Safety Analysis Set 
 
Table 14.3.1.12 Summary of Treatment-Emergent Adverse Events Potentially Pertaining to Drug Withdrawal 
Symptoms by MedDRA System Organ Class and Preferred Term During the Treatment Period- Safety Analysis Set 
 
Table 14.3.1.13 Summary of Treatment-emergent Adverse Events Potentially Pertaining to Drug Withdrawal 
Symptoms During the Safety Follow-up Period for Subjects Who Entered into the Safety Follow-up Period  
 
Table 14.3.1.14 Summary of Treatment-Emergent Adverse Events Potentially Pertaining to Injection Site Reactions by 
MedDRA System Organ Class and Preferred Term During the Treatment Period- Safety Analysis Set 
Table 14.3.1.15 Summary of Treatment-Emergent Adverse Events Potentially Pertaining to Acute Pancreatitis by 
MedDRA System Organ Class and Preferred Term during the Treatment Period - Safety Analysis Set 
 
Table 14.3.1.16 Summary of Treatment-Emergent Adverse Events Potentially Pertaining to Hepatic Disorders by 
MedDRA System Organ Class and Preferred Term during the Treatment Period - Safety Analysis Set 
 
Table 14.3.1.17 Summary of Treatment-Emergent Adverse Events Potentially Pertaining to Respiratory Depression 
and Failure by MedDRA System Organ Class and Preferred Term during the Treatment Period - Safety Analysis Set 
 
Table 14.3.1.18 Summary of Treatment-Emergent Adverse Events Potentially Pertaining to Central Nervous System 
Depression by MedDRA System Organ Class and Preferred Term during the Treatment Period - Safety Analysis Set 
 
Table 14.3.1.19 Summary of Treatment-Emergent Adverse Events Potentially Pertaining to Orthostatic Hypotension 
by MedDRA System Organ Class and Preferred Term during the Treatment Period - Safety Analysis Set 
 
Table 14.3.1.20 Summary of Treatment-Emergent Adverse Events Regarding Psychiatry History Topic by MedDRA 
System Organ Class and Preferred Term during the Treatment Period - Safety Analysis Set 
 
Table 14.3.2.1 Early Removal of Study Drug Depot  – Safety Analysis Set 
 
Table 14.3.3.1 Summary of Local Injection Site Tolerability Reactions During the Treatment Period- Safety Analysis Set  
Figure 14.3.3.1 Percentage of Subjects Who Reported Local Injection Site Tolerability Reactions: Pain - Safety Analysis 
Set 
 
Table 14.3.3.2 Summary of Local Injection Site Visual Analog Scale (VAS) Pain Scores - Safety Analysis Set 
 
Figure 14.3.3.2 Mean Value of Local Injection Site Visual Analog Scale (VAS) Pain Scores by visit - Safety Analysis Set 
 
Table 14.3.3.3 Summary of Local Injection Site Burning/Stinging Evaluation - Safety Analysis Set 
 
Table 14.3.3.4 Summary of Injection Site Evaluation During the Treatment Period: Attempted Removal - Safety 
Analysis Set 
 
Table 14.3.4.1 Incidence of Columbia Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation and Suicidal Behavior - 
Safety Analysis Set  
Table 14.3.4.2 Shift Table to Demonstrate Change in C-SSRS Categories from Baseline Lifetime During the Treatment 
Period - Safety Analysis Set 
 
Table 14.3.4.3 Shift Table to Demonstrate Change in C-SSRS Categories from Baseline 6 months During the Treatment 
Period - Safety Analysis Set 
 


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Table 14.3.4.4 Shift Table to Demonstrate Change in C-SSRS Scores from Baseline lifetime During the Treatment 
Period - Safety Analysis Set 
 
Table 14.3.4.5 Shift Table to Demonstrate Change in C-SSRS Scores from Baseline 6 months During the Treatment 
Period - Safety Analysis Set 
 
14.3.5 Laboratory Data Tables 
 
Table 14.3.5.1 Summary of Laboratory Data by Visit: Hematology - Safety Analysis Set 
 
Table 14.3.5.2 Summary of Laboratory Data by Visit: Serum Chemistry - Safety Analysis Set 
 
Table 14.3.5.3 Summary of Laboratory Data by Visit: Urinalysis - Safety Analysis Set 
 
Table 14.3.5.4 Summary of Potential Hepatotoxicity by Visit: Serum Chemistry - Safety Analysis Set 
 
Figure 14.3.5.4.1 Evaluation of Drug-Induced Serious Hepatotoxicity: Plot of Peak Total Bilirubin [x ULN] vs. Peak 
Aspartate Aminotransferase [x ULN] on a log/log scale During the Treatment Period – Safety Analysis Set 
 
Figure 14.3.5.4.2 Evaluation of Drug-Induced Serious Hepatotoxicity: Plot of Peak Total Bilirubin [x ULN] vs. Peak 
Alanine Aminotransferase [x ULN] on a log/log scale During the Treatment Period – Safety Analysis Set 
 
Figure 14.3.5.4.3 Evaluation of Drug-Induced Serious Hepatotoxicity: Box Plot to Assess Clinical Liver Safety Data by 
maximum Change from Baseline at Any Time During the Treatment Period– Safety Analysis Set 
Table 14.3.5.5 Summary of Observed Laboratory Data: Shift from Baseline: Hematology – Safety Analysis Set 
Table 14.3.5.6 Summary of Observed Laboratory Data: Shift from Baseline: Serum Chemistry – Safety Analysis Set 
 
Table 14.3.5.7 Summary of Observed Laboratory Data: Shift from Baseline: Urinalysis – Safety Analysis Set 
 
Table 14.3.5.8 Summary of Vital Signs by Visit – Observed Value and Change from Baseline – Safety Analysis Set 
Table 14.3.5.9 Body Weight, BMI, Waist Circumference, Hip Circumference and Waist-to-Hip Ratio – Observed Value – 
Safety Analysis Set 
 
Listings   
 
Listing 16.2.1 Subject Analysis Sets, Disposition, Completion of Study/Discontinuation from Study – All Screened 
Subjects  
Listing 16.2.2 Inclusion/Exclusion Criteria 
 
Listing 16.2.3 Inclusion/Exclusion Criteria Not Met – Screen Failure subjects 
 
Listing 16.2.4 Important Protocol Deviations – Safety Analysis Set 
 
Listing 16.2.5 Demographic and Baseline Characteristics – All Screened Subjects 
 
Listing 16.2.6 Medical/Surgical History – Safety Analysis Set 
 
Listing 16.2.7 Substance Use History – Safety Analysis Set  
Listing 16.2.8 Study Drug Injection and Dosing – Safety Analysis Set  
Listing 16.2.9 Dose Adjustments – Safety Analysis Set 
Listing 16.2.10 Prior Medications – Safety Analysis Set 
 
Listing 16.2.11.1 Concomitant Medications During RBP-6000 Dosing – Safety Analysis Set 
Listing 16.2.11.2 Concomitant Medications Post RBP-6000 Dosing – Safety Analysis Set 
Listing 16.2.12 Counseling and Behavioral Therapy – Safety Analysis Set 
 
Listing 16.2.13 Deaths During the Study – All Screened Subjects 
 
Listing 16.2.14 Serious Adverse Events During the Study – All Screened Subjects 
 
Listing 16.2.15 Adverse Events During the Study – All Screened Subjects 
 
Listing 16.2.16 Adverse Events Leading to Discontinuation During the Treatment Period – Safety Analysis Set  
Listing 16.2.17 Local Injection Site Tolerability – Safety Analysis Set  
Listing 16.2.18 Severe/Life Threatening Local Injection Site Tolerability Results and Corresponding Visual Analog Scale 
(VAS) Scores – Safety Analysis Set 
 
Listing 16.2.19 Local Injection Site Visual Analog Scale (VAS) Pain Scores – Safety Analysis Set 
 
Listing 16.2.20 Local Injection Site Burning/Stinging Evaluation – Safety Analysis Set 
 
Listing 16.2.21 Injection Site Evaluation: Attempted Removal – Safety Analysis Set 
 


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Listing 16.2.22 Columbia Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation and Behavior – Safety Analysis Set 
 
Listing 16.2.23 Columbia Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation Scores – Safety Analysis Set  
Listing 16.2.24 Columbia Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation Intensity Rating – Safety Analysis Set 
(Subjects with a Suicidal Ideation) 
 
Listing 16.2.25 Treatment-Emergent Adverse Events Leading to Dose Reduction During the Treatment Period – Safety 
Analysis Set 
 
Listing 16.2.26 Laboratory Data: Hematology – Safety Analysis Set 
 
Listing 16.2.27 Laboratory Data: Serum Chemistry – Safety Analysis Set 
Listing 16.2.28 Laboratory Data: Urinalysis – Safety Analysis Set 
 
Listing 16.2.29 Screening Laboratory Data– Safety Analysis Set 
 
Listing 16.2.30 Urine Drug Screening – Safety Analysis Set  
Listing 16.2.31 Urine Pregnancy Test – Safety Analysis Set  
Listing 16.2.32 Subjects Who Met Potential Hepatotoxicity Criteria  – Safety Analysis Set 
Listing 16.2.33 Laboratory Data for Subjects Who Met Potential Hepatotoxicity Criteria (Any Time Post Baseline)– 
Safety Analysis Set  
Listing 16.2.34 Vital Signs – Safety Analysis Set 
 
Listing 16.2.35 Body Weight, BMI, Waist Circumference, Hip Circumference and Waist-to-Hip Ratio – Safety Analysis 
Set 
Listing 16.2.36 Listing of Actual Injection Days Over Time During the Treatment Period – Safety Analysis Set