Virginia Opioid Overdose Treatment InitiatVE
Phase: PHASE3
Conditions: Opioid Use Disorder
Sponsor: Virginia Commonwealth University

 
 
Title: Virginia Opioid overdose Treatment InitiatiVE (VOTIVE) 
 
NCT #: NCT03818399 
 
Document date: 10/23/20 
 
Document Type: Protocol and SAP 
 
 
 

  
 
23 October 2020  
 
 
 
 
 
Clinical Study Protocol 
 
Protocol Title: 
Virginia Opioid overdose Treatment 
InitiatiVE (VOTIVE)  
 
IND Number: 
141,348 
 
 
 
 
Protocol Revision Date: 
October 23, 2020 
 
Protocol Version: 
9.0 
 
 
 
 

 
 
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Protocol Title: 
Virginia Opioid overdose Treatment InitiatiVE (VOTIVE)  
 
Protocol Version 
Number: 
9.0 
Protocol Version 
Date: 
October 23, 2020 
 
I have read the protocol, including all appendices, and I agree that it contains all the necessary 
information for me and my staff to conduct this study as described. My staff and/or I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
International Council on Harmonisation E6 / Good Clinical Practice (ICH/GCP) guidelines and 
will make a reasonable effort to complete the study within the time designated. 
I agree to ensure all associates, colleagues, and employees delegated to assist with the conduct of 
the study are trained on this study protocol and amendments, other study-related materials, and 
are qualified to perform their delegated tasks.  I will provide all study personnel copies of the 
protocol and any amendments and grant access to all information provided by Indivior Inc. or 
specified designees. I will discuss the material with them to ensure that they are fully informed 
about the IMP and appropriate information throughout the study.  Mechanisms are in place to 
ensure that site staff receives the appropriate information throughout the study. 
 
 
 
 
 
  
Signed: 
 
 
Date:  
 
F. Gerard Moeller, MD 
 
 
23-October-2020 
Director, Institute for Drug and Alcohol Studies 
Virginia Commonwealth University 
 
 

 
 
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STUDY SYNOPSIS 
Protocol Title: 
Virginia Opioid overdose Treatment InitiatiVE (VOTIVE)  
Indivior Inc. Reference Number: INDV-6000-304 
Rationale:  
Individuals with opioid use disorder (OUD) who overdose (OD) on opioids have a high risk of 
repeat opioid OD. At the Virginia Commonwealth University (VCU) Medical Center, 
emergency department (ED) data between 2015 and the end of 2017 indicate that, on average, 
27% of individuals seen for an index opioid OD in the ED had a second event (OD or death 
due to opioid OD). Seventy percent of these events occurred within the first 6 months 
following the index episode with the majority occurring in the first 2 months post initial OD. 
Most likely due to the prevalence of fentanyl and fentanyl derivatives in heroin, the risk of 
fatality with opioid OD has risen exponentially in the United States (US) over the last several 
years (Mercado 2014). 
 
Treatment of OUD patients at high risk of OD (such as when released from incarceration), 
with methadone or buprenorphine reduces the risk of OD index cases by up to 85% 
(Marsden 2017). This study will assess whether OUD patients treated with SUBLOCADE™ 
(buprenorphine extended-release injection for subcutaneous use) in the ED, inpatient unit, or at 
the clinic within 7 days (168 h) of overdose after receiving a test dose of SUBOXONE® 
(buprenorphine and naloxone) following OD reversal with an opioid antagonist reduces 
subsequent opioid OD events (repeat OD and/or repeat OD with fatality) as compared to a 
historical control cohort and concurrent controls who decline treatment participation. The 
study will also provide data on feasibility of initiation of SUBLOCADE within 7 days (168 h) 
of an overdose and data on subsequent outpatient treatment engagement. 
Target Population: 
Adults with moderate to severe OUD (as defined by DSM-5 criteria) following an opioid OD, 
received treatment with an opioid antagonist, and are clinically stable for a screening 
interview. 
Number of Subjects:  100 
Duration of Treatment: 
The total duration of study participation will be approximately 7 months. Subjects will receive 
treatment for approximately 6 months with an End of Treatment (EOT) visit at 7 months post 
treatment initiation. 
 
Objective(s):  
The primary objective of this study is: 
• Determine the effect of SUBLOCADE treatment in the ED, inpatient unit or in the 
clinic within 7 days (168 h) after opioid OD on repeat OD and death compared to a 
historical control group and concurrent controls who decline treatment participation.  

 
 
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The key secondary objective of this study is:  
• Determine effect of SUBLOCADE administered in the ED, inpatient unit or in the 
clinic within 7 days (168 h) after OD on treatment engagement at 3 months and 6 
months.  
The exploratory objectives of this study are:  
• To determine the effect of SUBLOCADE administered in the ED, inpatient unit or in 
the clinic within 7 days (168 h) of opioid OD followed by SUBLOCADE in the clinic 
on opioid craving.  
• To determine the efficacy of SUBLOCADE that has been administered in the ED, 
inpatient unit or at the clinic within 7 days (168 h) of opioid OD followed by 
SUBLOCADE in the outpatient clinic on opioid use as determined by Urine Drug 
Screen (UDS).  
• To evaluate the effect of SUBLOCADE administered within 7 days (168 h) of an 
opioid OD followed by SUBLOCADE in the clinic on decision making using a delay 
discounting task and a brief opioid demand measure to measure craving valuation 
(hypothetical maximum price participants would be willing to pay for access to opioid, 
assessing craving/valuation).  
• To evaluate the association between participant genetic polymorphisms and subjects 
with history of OD in subjects that consent to the PGx sub-study. 
• To evaluate the relationship between genetics/behavioural laboratory measures of 
decision making and treatment outcome, including repeat OD in subjects that consent 
to the PGx sub-study.  
• To determine the relationship between decision making and treatment retention and 
illicit opioid use. 
• To evaluate healthcare resource utilisation associated with either treatment regimen as 
compared to the historical control (2015-2018) obtained from VCU anonymized health 
records.   
• To assess the impact of SUBLOCADE administered in the ED, inpatient unit or within 
7 days (168 h) of an opioid OD followed by administration of SUBLOCADE in the 
clinic on treatment effectiveness as measured by Treatment Effectiveness Assessment 
(TEA), on medication satisfaction as measured by the Medication Satisfaction 
Questionnaire (MSQ), and on employment, presentism and absenteeism as assessed by 
the Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem (WPAI:SHP). 
Study Design:  
This is a Phase 3b, open-label study in patients who are treated for an opioid OD and receive 
treatment with an opioid antagonist. The study is designed to determine effect of 
SUBLOCADE on repeat OD and death compared to historical control data.  
The study will assess subjects that receive acute administration of SUBOXONE sublingual 
film followed by SUBLOCADE administration in the 1) ED, 2) inpatient unit or 3) within 7 

 
 
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days (168 h) after OD in an affiliated outpatient treatment clinic combined with 6 months of 
treatment with SUBLOCADE in the outpatient treatment clinic compared to historical and 
concurrent control data from VCU electronic health records. The affiliated clinic will agree to 
see the subject on arrival at the clinic during normal clinic hours.  
Subjects will be given the opportunity to participate in an optional pharmacogenetics (PGx) 
sub-study. 
1) Patients presenting to the ED for an opioid OD who received treatment with an opioid 
antagonist and are considered clinically stable and alert (respiratory rate [RR] ≥ 12, 
pulse oximetry > 95%, Glasgow Coma Scale [GCS] score of 15), and, who deny 
recent/regular use of long acting opioids (e.g., methadone) will be approached 
regarding interest in study participation. Written informed consent will only be 
obtained if the patient’s judgement is intact as determined clinically by the Investigator 
or a medically qualified sub-investigator or research nurse. This OD will be considered 
the index OD. 
 
Participants who meet inclusion/exclusion criteria will be administered 4 mg/1 mg 
SUBOXONE sublingual film in the ED followed by a 1-hour wait. If the subject 
displays no allergic/hypersensitivity reaction to SUBOXONE sublingual film after 
1 hour, SUBLOCADE (300 mg) will be administered in the ED. Subjects will remain 
in the ED for 1 hour after the 300 mg SUBLOCADE injection and are clinically stable 
(respiratory rate [RR] ≥12, pulse oximetry > 95%, Glasgow Coma Scale [GCS] score 
of 15). A COWS assessment and AEs will be collected prior to SUBLOCADE 
administration and 1-hour post SUBLOCADE prior to discharge. Participants with 
initial COWS <8 and who were released from a controlled environment within the past 
30 days, will remain in the ED for 2 hours after SUBLOCADE to assess for sedation 
using the Richmond Agitation-Sedation Scale. Patients will be discharged if RAS is 0 
or greater. Patients who present with abnormal vital signs, or sign of sedation will 
remain in ED until they meet the ED discharge criteria. If participants experience 
precipitated withdrawal they will be treated symptomatically with medication as 
described in section 8.4 below.  
Upon ED discharge, patients will be instructed to use over the counter ibuprofen and 
acetaminophen as needed. They will also be provided with two oral doses of 50 mg of 
hydroxyzine as ancillary medications if needed in the judgement of the clinician. The 
subject will receive referral to an outpatient treatment clinic affiliated with the hospital 
system in which the ED resides. 
 
Patients presenting to the ED for an opioid OD who received treatment with an opioid 
antagonist and who are not approached by the study team for enrollment (e.g. OD 
outside of regular business hours) will be given a referral card by a ED healthcare 
provider to go to the outpatient clinic for an initial screening visit. Subjects must arrive 
at the clinic within 7 days (168 h) of OD.  
 

 
 
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2) Patients presenting to the ED for an opioid OD who received treatment with an opioid 
antagonist and who are admitted to an inpatient unit will be approached regarding 
interest in study participation. Patients who are considered clinically stable and alert 
(respiratory rate [RR] ≥ 12, pulse oximetry >95%, [GCS] score of 15), who deny 
recent/regular use of long-acting opioids (e.g. methadone) will be approached. Written 
informed consent will only be obtained if the patient’s judgement is intact and there are 
no other serious underlying medical complications as determined clinically by the 
Investigator or a medically qualified sub-investigator or research nurse.    
 
Participants  who meet inclusion/exclusion criteria will be administered a 4 mg/1 mg 
SUBOXONE sublingual film followed by a 1-hour wait. If the participant displays no 
allergic/hypersensitivity reaction to SUBOXONE sublingual film after 1 hour, 
SUBLOCADE (300 mg) will be administered on the inpatient unit. Participants will 
remain in the inpatient unit for 1 hour after the 300 mg SUBLOCADE injection and are 
clinically stable (respiratory rate [RR] ≥12, pulse oximetry > 95%, Glasgow Coma 
Scale [GCS] score of 15. A COWS assessment and AEs will be collected prior to 
SUBLOCADE administration and 1-hour post SUBLOCADE. Participants with initial 
COWS <8 and who were released from a controlled environment within the past 30 
days, will remain in the inpatient unit for 2 hours after 300 mg SUBLOCADE to assess 
for sedation using the Richmond Agitation-Sedation Scale. Patients will be discharged 
if RAS is 0 or greater. Patients who present with abnormal vital signs, or sign of 
sedation will remain in the inpatient unit.  If participants experience precipitated 
withdrawal they will be treated symptomatically with medication as described in 
section 8.4 below. 
 
Upon discharge, patients will be instructed to use over the counter ibuprofen and 
acetaminophen as needed. They will also be provided with two oral doses of 50 mg of 
hydroxyzine as ancillary medications if needed in the judgement of the clinician. The 
subject will receive referral to an outpatient treatment clinic affiliated with the hospital 
system in which the inpatient unit resides.  
 
Patients presenting to the ED for an opioid OD who received treatment with an opioid 
antagonist, who are admitted to the inpatient unit and who are not approached by the 
study team for enrollment(e.g. discharge outside of regular business hours) will be 
given a referral card to go to the outpatient clinic by a healthcare provider for an initial 
screening visit. Subjects must arrive at the clinic within 7 days (168 h) of OD.  
 
3) Patients who are seen only by EMS personnel and are given an opioid antagonist for 
opioid OD but refuse transport to an Emergency Department but would like to be 
considered for the VOTIVE study will be given a referral card by EMS personnel. 
Patients who present to the ED or who are admitted to the inpatient unit for an Opioid 
OD and would like to be considered for the VOTIVE study but who are not approached 
by the study team (i.e. outside of business hours) will be given a referral card by a 
healthcare provider.  The patient may present to the clinic within 7 days (168 h) of OD 
event for evaluation and initial screening visit.  
 

 
 
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In the clinic, subjects will be consented if they express interest in participating in the 
study. If participants meet study inclusion criteria and none of the exclusion criteria 
they will be administered 4 mg/1 mg SUBOXONE sublingual film followed by a 1-
hour wait. If the subject displays no allergic/hypersensitivity reaction to SUBOXONE 
sublingual film after 1 hour, SUBLOCADE (300 mg) will be administered in the clinic. 
Subjects will remain in the clinic for 1 hour after the SUBLOCADE injection and are 
clinically stable (respiratory rate [RR] ≥12, pulse oximetry > 95%, Glasgow Coma 
Scale [GCS] score of 15. A COWS assessment and AEs will be collected prior to 
SUBLOCADE administration and 1-hour post SUBLOCADE prior to discharge. 
Participants with initial COWS <8 and who were released from a controlled 
environment within the past 30 days, will remain in the outpatient clinic for 2 hours 
after 300 mg SUBLOCADE to assess for sedation using the Richmond Agitation-
Sedation Scale. Patients will be discharged if RASS is 0 or greater. Patients who 
present with abnormal vital signs, or sign of sedation will remain in clinic or will be 
transferred to the ED until they are safe for discharge from the medical facility. If 
participants experience precipitated withdrawal, they will be treated symptomatically 
with medication as described in section 8.4 below.   
 
Upon discharge, patients will be instructed to use over the counter ibuprofen and 
acetaminophen as needed. They will also be provided with two oral doses of 50 mg of 
hydroxyzine as ancillary medications if needed in the judgement of the clinician. 
 
Once subjects are engaged in care at the treatment clinic, they will continue to receive 
SUBLOCADE for 6 months. The second 300 mg injection will be administered on Day 8(-
0/+4 days) after the first injection, with subsequent 300 mg injections administered at 28-day 
(-2/+4 days) intervals over approximately 6 months for a total of 7 injections. If necessary, for 
tolerability, the dose of SUBLOCADE can be reduced to 100 mg.  All subjects will receive 
site standard psychosocial therapy at least weekly during the first 3 months of treatment, and 
twice monthly thereafter if clinically stable.   
All subjects will complete an End of Treatment (EOT) / Early Termination (ET) visit 28 days 
after their last injection of SUBLOCADE. Within 3 months prior to or at the EOT visit, the 
Investigator or a medically qualified sub-investigator will discuss the subject’s available 
treatment options and arrange referral. All subjects will receive a safety follow-up telephone 
call, 30 days after their EOT/ET visit to assess AEs, SAEs, pregnancy status (if applicable) 
and concomitant medications. Subjects who decline to continue in medication assisted 
treatment (MAT) will receive monthly safety follow-up phone calls for an additional 5 months 
(6 months total) to assess SAEs, pregnancy status (if applicable) and concomitant medications. 
Primary Endpoint(s):  
The primary endpoint of this study is: 
• Time to repeat OD or opioid-related death. Repeat OD or opioid-related death will be 
measured from electronic medical records and state death registries. 
• Additional comparisons on repeat OD and death rates will be made to concurrent 
patients who decline to participate in the SUBLOCADE injection. 

 
 
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Secondary Endpoint(s):  
The key secondary endpoint of the study is:  
• Treatment engagement as measured by attending the outpatient clinic and receiving 
subsequent buprenorphine treatment at 3 and 6 months.  
The secondary endpoints of this study are: 
• Numbers and percent of subjects in treatment at 3 and 6 months after opioid OD. 
Exploratory Endpoints:  
The exploratory endpoints of this study are: 
• Opioid craving in subjects as measured by Craving Visual Analog Scale (VAS) scores. 
• Illicit opioid use as measured by urine drug screen (UDS) results. 
• Genetic predictors of treatment response and OD. 
• Predictability of treatment response based on impulse control as measured by decision 
making in the delay discounting task, and opioid cravings/valuation as measured by the 
brief opioid demand task. 
• Healthcare resource utilisation as compared to the historical control (2015-2018) 
obtained from VCU anonymized health records.   
• Treatment effectiveness as measured by Treatment Effectiveness Assessment (TEA), 
medication satisfaction as measured by the Medication Satisfaction Questionnaire 
(MSQ), and employment, presentism and absenteeism as assessed by the Work 
Productivity and Activity Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP). 
Safety Assessments:  
Safety assessments include the proportion of subjects with AEs of the following types at any 
time during the treatment period: at least 1 AE, a drug-related AE, an SAE, a serious and drug-
related AE, or an AE leading to treatment discontinuation. 
Additional safety assessments include laboratory assessments, brief physical examinations, 
vital signs and concomitant medications. Worsening or initiation of withdrawal symptoms, 
based on observation and subject self-report, will be evaluated during Visit 1 (ED, inpatient 
unit or Clinic) after SUBOXONE and SUBLOCADE. If participants experience precipitated 
withdrawal, they will be treated symptomatically with medication as described in section 8.4 
below. 
Health Economics and Outcomes Assessments: 
Health economics and outcomes assessments include the include Healthcare Resource 
Utilization questionnaire (HCRU), the Treatment Effectiveness Assessment (TEA), the 
Medication Satisfaction Questionnaire (MSQ), and Work Productivity and Activity 
Impairment Questionnaire: Specific Health Problem (WPAI-SHP). 
Statistical Methods:  
Prospective Analyses for the Primary and Key Secondary Endpoints: 

 
 
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The primary endpoint, numbers of subjects who have a repeat OD or OD related death will be 
analysed using a Cox proportional hazards model controlling for route of administration and 
comorbid substance use disorder compared to a historical control group and to concurrent 
subjects who decline SUBLOCADE treatment. 
The secondary endpoint, treatment engagement as measured by attending the outpatient clinic 
and receiving subsequent buprenorphine treatment at 3 and 6 months will be analysed using a 
Cox proportional hazards model comparing patients with primarily intravenous vs non-
intravenous routes of opioid use.  
Planned Analyses: 
The primary analysis will be performed on the primary and key secondary endpoints after all 
subjects have been enrolled and completed the end of treatment visit. An enrolled subject is 
defined as a subject who has received at least one dose of SUBLOCADE. 
 

 
 
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STUDY SCHEMATIC 
Figure 1 
Study Schematic for SUBLOCADE Initiated in Emergency 
Department 
 
 
 
 
 
a. Participants who decline to be enrolled in the study will receive care as determined by the 
ED physicians and continue to be passively followed for 24 weeks. Passive follow-up 
will include tracking for treatment initiation and engagement and repeat OD via 
anonymized medical records and tracking for death using state death registries.  
b. Injection 2 will be 300 mg and will occur on Day 8 (-0 /+4 days); Injections 3-7 will 
remain 300 mg (or 100 mg if unable to tolerate 300 mg as determined by study 
investigator) administered at 28-day (-2/+4 days) intervals.   
c. Intervention subjects will receive a safety follow-up telephone call 30 days after their 
EOT/ET visit to assess AEs, SAEs, pregnancy status (if applicable) and concomitant 
medications. Subjects who decline to continue in MAT will receive monthly safety 
follow-up phone calls for an additional 5 months (6 months total) to assess SAEs, 
pregnancy status (if applicable) and concomitant medications. 
 
 
 
 
 
 
 
Week 1 Day 1 
Emergency Department 
Consent + Screening 
End of Treatment 
(Week 24) 
Approached to 
Participante in 
Study 
SUBLOCADEb 
+ Counselling 
End of Study Safety  
Telephone Follow up 
(Week 28)c 
Week1 Day 2 – Week 24  
Clinic  
 
Week 28  
SUBOXONE test 
dose + 
SUBLOCADE 
Administration + 
Treatment 
Referral 
ED determined care 
Passive Follow-up 
Decline studya 
Screen fail 

 
 
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Figure 2 
Study Schematic for SUBLOCADE Initiated in Inpatient Unit 
 
 
 
 
 
a. Participants who decline to be enrolled in the study will receive follow-up care as 
determined by the inpatient unit physicians and continue to be passively followed for 24 
weeks. Passive follow-up will include tracking for treatment initiation and engagement 
and repeat OD via anonymized medical records and tracking for death using state death 
registries.  
b. Injection 2 will be 300 mg and will occur on Day 8 (-0/+ 4); Injections 3-7 will remain 
300 mg (or 100 mg if unable to tolerate 300 mg as determined by study investigator) 
administered at 28-day (-2/+ 4 days) intervals.   
c. Intervention subjects will receive a safety follow-up telephone call 30 days after their 
EOT/ET visit to assess AEs, SAEs, pregnancy status (if applicable) and concomitant 
medications. Subjects who decline to continue in MAT will receive monthly safety 
follow-up phone calls for an additional 5 months (6 months total) to assess SAEs, 
pregnancy status (if applicable) and concomitant medications. 
 
 
Week 1 Day 1 
Inpatient Unit 
Consent + Screening 
End of Treatment 
(Week 24) 
Approached to 
Participante in 
Study 
SUBLOCADEb
™ + Counselling 
End of Study Safety  
Telephone Follow up 
(Week 28)c 
Week1 Day 2 – Week 24  
Clinic  
 
Week 28  
SUBOXONE test 
dose + 
SUBLOCADE 
Administration + 
Treatment 
Referral 
Inpatient determined 
follow-up 
Passive Follow-up 
Decline studya 
Screen fail 

 
 
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Figure 3 
Study Schematic for Initial Dose of SUBLOCADE in Clinic 
 
 
 
 
 
a. Participants who decline to be enrolled in the study will receive care as determined by the 
ED physicians and continue to be passively followed for 24 weeks. Passive follow-up 
will include tracking for treatment initiation and engagement and repeat OD via 
anonymized medical records and tracking for death using state death registries. 
b. Consent and screening at the clinic will include all procedures that take place in the ED 
for participants who are enrolled in the ED.   
c. Injection 2 will be 300 mg and will occur on Day 8 (-0 /+4 days); Injections 3-7 will 
remain 300 mg (or 100 mg if unable to tolerate 300 mg as determined by study 
investigator) administered at 28-day (-2/+ 4days) intervals.   
d. Intervention subjects will receive a safety follow-up telephone call 30 days after their 
EOT/ET visit to assess AEs, SAEs, pregnancy status (if applicable) and concomitant 
medications. Subjects who decline to continue in MAT will receive monthly safety 
follow-up phone calls for an additional 5 months (6 months total) to assess SAEs, 
pregnancy status (if applicable) and concomitant medications. 
 
 
 
 
 
Week 1 Day 1 
Emergency Department or 
Ambulance 
End of Treatment 
(Week 24) 
Status Post Opioid 
OD Treated with 
Opioid Antagonist 
but Refuses 
Transport to ED or  
not approached by 
study team in ED or 
inpatient unit. Given 
Referral to Clinic 
within 7 days (168 
h) of OD 
SUBLOCADEc 
+ Counselling 
End of Study Safety  
Telephone Follow up 
(Week 28)d 
Within 7 days (168 h)after OD – Week 
24  
 
Week 28  
Arrival to Clinic 
Consent, 
bScreening. 
SUBOXONE test 
dose + 
SUBLOCADE 
Administration + 
Treatment  
  
Passive Follow-up 
Decline referrala 

 
 
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Table of Contents 
CLINICAL PROTOCOL SIGNATURE PAGE 
2 
SYNOPSIS 
3 
TABLE OF CONTENTS  
13 
 
LIST OF IN-TEXT TABLES 
16 
LIST OF IN-TEXT FIGURES 
16 
LIST OF ABBREVIATIONS 
17 
1.  INTRODUCTION AND RATIONALE 
19 
  1.1  Background and Rationale 
19 
     1.1.1  Investigational Medicinal Product 
19 
     1.1.2  Dose Rationale 
19 
     1.1.3  Clinical Adverse Event Profile 
20 
  1.2  Benefit-Risk Summary   
21 
2.  STUDY OBJECTIVES 
22 
  2.1  Primary 
22 
  2.2  Secondary  
22 
  2.3 Exploratory 
22 
3.  STUDY ENDPOINTS 
24 
  3.1  Primary  
24 
  3.2  Secondary 
24 
  3.3  Exploratory 
24 
  3.4  Safety Assessments 
24 
  3.5  Health Economics and Outcomes Assessments 
25 
  3.6  Hypothesis and Treatment Comparisons 
25 
4.  STUDY PLAN 
26 
  4.1  Study Design 
26 
  4.2  Duration of Treatment 
26 
5.  STUDY POPULATION SELECTION 
27 
  5.1  Number of Subjects 
27 
  5.2  Inclusion Criteria 
27 
  5.3  Exclusion Criteria 
27 
  5.4  Initial SUBLOCADE Dosing Criteria 
28 
6  STUDY CONDUCT 
29 
     6.1  Subject Enrollment 
29 
     6.2  Screen Failure 
29 
     6.3  Subject Completion 
29 
       6.3.1  Treatment Completion 
29 
     6.4  Withdrawal and Stopping Criteria 
29 
       6.4.1  Subject Withdrawal from Treatment 
29 
       6.4.2  Subject Withdrawal from the Study 
30 
       6.4.3  Subject Withdrawal of Consent 
30 
       6.4.4  Subjects Lost to Follow-up 
30 
       6.4.5  Liver Chemistry Stopping Criteria 
30 
7.  STUDY SUSPENSION OR TERMINATION 
32 

 
 
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8.  DESCRIPTION OF STUDY PROCEDURES 
33 
     8.1  Demographics and Medical History 
33 
       8.1.1  Mini-International Neuropsychiatric Interview (DSM5; OUD).  
33 
     8.2 Physical Examination 
34 
     8.3  Vital Signs  
34 
     8.4  Treatment of Precipitated Withdrawal  
34 
8.5 Clinical Laboratory Tests   
35 
       8.6.1  Sample Collection, Storage, and Shipping 
36 
     8.6  Efficacy Assessments 
36 
       8.6.1  Urine Drug Screen 
36 
       8.6.2  Opioid Craving Visual Analog Scale (OC-VAS) 
36 
     8.7  Supportive Assessments 
36 
       8.7.1  Delay Discounting Task 
36 
       8.7.2  Opioid Demand Task 
36 
       8.7.3  Clinical Opiate Withdrawal Scale (COWS) 
37 
     8.8  Pharmacogenomic Assessment 
37 
     8.9  Health Economics and Outcomes Assessments 
37 
       8.9.1  Treatment Effectiveness Assessment (TEA) 
37 
       8.9.2  Healthcare Resource Utilization (HCRU) Questionnaire 
37 
       8.9.3  Medication Satisfaction Questionnaire 
38 
       8.9.4  Work Productivity and Activity Impairment Questionnaire:  
                 Specific Health Problem (WPAI: SHP) 
38 
     8.10  Appropriateness of Measurements 
38 
     8.11 Protocol Deviations 
38 
9.  STUDY DRUG MANAGEMENT 
39 
     9.1  Description 
39 
       9.1.1  Study Treatments 
39 
       9.1.2 SUBLOCADE 
39 
       9.1.3  SUBOXONE Sublingual Film 
39 
       9.1.4  Blinding 
39 
    9.2 Packaging and Storage 
39 
    9.3  Drug Administration 
40 
       9.3.1  SUBLOCADE Injection 
40 
       9.3.2  SUBOXONE Sublingual Film 
40 
     9.4  Accountability 
41 
     9.5  Reporting Product Complaints 
41 
     9.6 Concomitant Therapies  
42 
       9.6.1  Permitted Concomitant Therapies 
42 
       9.6.2  Drug-Drug Interactions 
42 
       9.6.3  Prohibited Concomitant Therapies 
42 
     9.7  Compliance 
43 
10.  ADVERSE EVENTS 
44 
     10.1  Assessment of Adverse Events 
45 
       10.1.1  Time Period for Collecting Adverse Events 
45 
       10.1.2  Assessment of Intensity 
45 

 
 
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       10.1.3  Assessment of Causality 
46 
       10.1.4  Clinical Laboratory Changes 
46 
11.  SERIOUS ADVERSE EVENTS 
48 
     11.1  Documenting Serious Adverse Events 
49 
     11.2  Reporting Serious Adverse Events    
49 
       11.2.1 Reporting of Serious Adverse Events 
49 
       11.2.2  Regulatory Reporting Requirements for SAES 
50 
       11.2.3  Overdose 
50 
       11.2.4. Depot removal 
50 
12.  PREGNANCY 
51 
     12.1  Collecting and Reporting Pregnancy Information 
51 
     12.2  Action to be Taken if Pregnancy Occurs in a Female Subject 
51 
13.  DATA MANAGEMENT 
52 
     13.1  Data Collection and Management 
52 
       13.1.1  Historical Control Data 
52 
       13.1.2  Database Quality Assurance 
52 
       13.1.3  Source Documents 
53 
14.  STATISTICS 
54 
     14.1  General Procedures  
54 
     14.2  Sample Size 
54 
     14.3  Statistical Hypotheses 
55 
       14.3.1  Primary Endpoint 
55 
     14.4  Analysis Populations 
55 
       14.4.1  Treatment Population 
55 
     14.5  Planned Analysis 
55 
     14.6  Demographic and Baseline Characteristics Analyses 
55 
     14.7  Efficacy Analysis 
55 
       14.7.1  Primary Efficacy Analysis 
55 
       14.7.2  Secondary/Exploratory Endpoint Analysis  
56 
       14.7.3  Exploratory Analysis  
58 
       14.7.4  Subgroup Analysis  
59 
     14.8  Handling of Missing Data 
59 
     14.9  Analysis of Safety 
59 
       14.9.1  Adverse Events 
59 
       14.9.2 Extent of Exposure 
59 
       14.9.3  Laboratory Data 
60 
       14.9.4  Vital Signs 
60 
       14.9.5  Other Safety-Related Variables 
60 
15.  ETHICS AND RESPONSIBILITIES 
61 
     15.1  Good Clinical Practice 
61 
     15.2  Institutional Review Board 
61 
     15.3  Informed Consent 
61 
     15.4  Records Management 
61 
16.  AUDITING AND MONITORING 
63 
17.  AMENDMENTS 
64 

 
 
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18.  STUDY REPORTS AND PUBLICATIONS 
65 
19.  STUDY TERMINATION 
66 
20.  CONFIDENTIALITY   
67 
21.  REFERENCES 
68 
22.  APPENDICES 
71 
     22.1  Appendix 1- Schedule of Events- Visit 1 (In Ed, Inpatient Unit, or 
Outpatient Clinic with 7 days of OD) 
              (Week 1 Day 1)  
71 
     22.2  Appendix 2- Treatment Clinic Schedule of Events (Week 1 Day 2-  
              Week 55 Day 381) 
73 
     22.3  Appendix 3-  Liver Safety 
75 
  
List of In-Text Tables 
Table 1 
List of Laboratory Tests ...............................................................................35 
Table 2 
Summary of Efficacy Analysis Strategy ......................................................57 
 
List of In-Text Figures 
Figure 1 
Study Schematic...........................................................................................10 
 
 
 

 
 
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List of Abbreviations 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUD 
Alcohol Use Disorder  
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CRF/eCRF 
case report form/electronic case report form 
ECG 
electrocardiogram 
ED 
emergency department 
EOT 
end of treatment 
EOS 
end of study 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HCRUQ 
Healthcare Resource Utilization Questionnaire 
HEOR 
Health Economics Outcomes Research  
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation Technical Requirements for 
Pharmaceuticals for Human Use  
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product  
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 

 
 
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MedDRA 
Medical Dictionary for Regulatory Activities  
M.I.N.I. 
Mini-International Neuropsychiatric Interview 
MSQ 
Medication Satisfaction Questionnaire 
OC-VAS 
Opioid Craving Visual Analog Scale  
OD 
overdose 
OUD 
opioid use disorder 
PGx 
pharmacogenomic(s) 
PI 
Principal Investigator 
PK 
PV 
pharmacokinetic(s) 
pharmacovigilance 
RASS 
Richmond Agitation-Sedation Scale  
SAE 
serious adverse event 
SUD 
Sedative, Hypnotic or Anxiolytic Use Disorder  
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction  
TEA 
Treatment Effectiveness Assessment 
ULN 
upper limit of normal 
UDS 
urine drug screen 
US 
United States 
USPI 
US Prescribing Information 
VCU 
Virginia Commonwealth University 
WBC 
white blood cell (count) 
WHO 
World Health Organization 
WHODD 
WPAI-SHP 
 
WHO Drug Dictionary 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem 

 
 
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1 
INTRODUCTION AND RATIONALE 
1.1 
Background and Rationale  
The study will be carried out in accordance to the protocol and with local legal and regulatory 
requirements, ICH/GCP and all applicable subject privacy requirements. 
1.1.1 
Investigational Medicinal Product 
SUBLOCADETM (buprenorphine extended-release) injection is a colorless to amber sterile 
solution for SC injection designed to deliver buprenorphine at doses of 100 mg or 300 mg at a 
controlled rate over a one-month period. The active ingredient in SUBLOCADE injection is 
buprenorphine free base, a mu-opioid receptor partial agonist and a kappa-opioid receptor 
antagonist. Buprenorphine is dissolved in the ATRIGEL® delivery system at 18% by weight and 
is a biodegradable 50:50 poly (DL-lactide-co-glycolide) polymer and a biocompatible solvent, 
N-methyl-2-pyrrolidone (NMP). Refer to the SUBLOCADE Investigator’s Brochure (IB) or US 
prescribing information (USPI) for additional information on the physical and chemical 
properties of the drug substance and for a list of excipients. 
Adequate precautions must be taken to avoid direct contact with the product. Occupational 
hazards and recommended handling procedures are provided in the USPI.   
SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo. 
Each SUBOXONE sublingual film contains buprenorphine HCl and naloxone HCl dihydrate at a 
4:1 ratio expressed as the free bases. Films are intended for sublingual or buccal administration 
and are available in 4 dosage strengths (2 mg/0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg). 
Refer to the SUBOXONE Sublingual Film USPI for additional information on the physical and 
chemical properties of the drug substance and for a list of excipients. 
1.1.2 
Dose Rationale 
SUBLOCADE:  SUBLOCADE is intended to be administered in this study as 300 mg monthly 
doses. If subjects are unable to tolerate the 300 mg dose as determined by the study investigator, 
the dose may be reduced to 100 mg monthly. The SUBLOCADE doses selected for this study 
have been shown to be efficacious in study RB-US-13-0001 (Double-Blind Efficacy). The doses 
tested in study RB-US-13-0001 were chosen to achieve and maintain patients at plasma 
exposures (≥ 2 ng/mL) that would achieve ≥ 70% brain mu-opioid receptor occupancy. This 
target plasma level and mu-opioid receptor occupancy was chosen based on data published by 
Greenwald (Greenwald 2003; Greenwald 2007) which showed that these levels were required to 
adequately control opioid withdrawal symptoms, opioid craving and to block the drug liking 
effects of an agonist when injected. Study RB-US-13-0002 (Opioid Blockade) showed that two 
300 mg doses of SUBLOCADE injection dosed a month apart blocked the drug liking effects of 
an agonist when injected after treatment initiation with SUBLOCADE injection. However, wide 
variation can be seen in isolated measurements from individual subjects. Further details can be 
found in the IB and USPI. 

 
 
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The hypothesis is that SUBLOCADE will reduce the risk of a repeat opioid OD. This hypothesis 
is based on data showing that buprenorphine plasma exposures above 2 ng/ml will reduce the 
risk of an opioid OD in patients with OUD. Exposure-response relationships were assessed for 
illicit opioid use, and withdrawal symptoms using data obtained from 489 opioid dependent 
patients in the double-blind Phase 3 Study (RB-US-13-0001). PK data from the RB-US-13-0001 
study show average buprenorphine plasma concentrations were below 2 ng/mL by 2 weeks after 
the first 300 mg injection. Average concentrations increased to greater than 2 ng/mL after the 
second 300 mg injection and remained above through to the 3rd injection, 28 days later.  
To increase potential benefit in this population, the second 300 mg SUBLOCADE injection will 
be administered on day 8 (-0/+4 days) with subsequent injections being administered at 28-day (-
2 / +4days of scheduled dosing days) intervals over approximately 6 months. Safety data from 
the SUBLOCADE Phase 3 program indicates this will not be a safety concern (average 
buprenorphine concentrations after the second 300 mg injection were lower than those observed 
at steady state).  
SUBOXONE Sublingual Film:  A single test dose of 4 mg/1mg SUBOXONE sublingual film 
will be administered to subjects in the ED prior to administration of the SUBLOCADE injection 
to ensure no allergic reaction or hypersensitivity to buprenorphine is present. This dose was 
selected as the targeted population have received an opioid antagonist for the treatment of an OD 
and are expected to be experiencing significant withdrawal symptoms.  
1.1.3 
Clinical Adverse Event Profile 
The safety profile of SUBLOCADE injection observed in the Phase 3 studies (RB-US-13-0001, 
RB-US-13-0003 and INDV-6000-301) was generally consistent with the known safety profile of 
buprenorphine administered by the sublingual (SL) or buccal routes for the treatment of OUD 
with the expected exception of injection site tolerability and reactions.   
The most common ADRs (reported by ≥5% of subjects) with SUBLOCADE were constipation, 
nausea, hepatic enzyme increased, headache, injection site pain, injection site pruritus, vomiting 
and fatigue. Injection site reactions were generally mild to moderate in severity, and none were 
serious. There were no unexpected safety findings. There was no increased risk of suicidality, 
and opioid OD was reported in <1% of subjects. There were no cases of SUBLOCADE injection 
OD reported. There was 1 death reported in the clinical development program, an SAE of 
gunshot wound with an outcome of death considered not related to study treatment and homicide 
by the police. There were no reports of subjects who attempted to remove the depot and no 
reports of buprenorphine OD or respiratory depression. No clinically significant trends in vital 
signs, electrocardiograms (ECGs), clinical laboratory tests or physical examinations have been 
noted in any of these studies. 
The safety profile of SUBOXONE sublingual film is well characterized and, with the exception 
of the injection site reactions described above, is similar to that of SUBLOCADE. 

 
 
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1.2 
Benefit-Risk Summary 
Patients with OUD who survive an OD are at high risk of a subsequent OD. Treatment of OUD 
patients at high risk of OD (such as when released from incarceration), with methadone or 
buprenorphine reduces the risk of OD index cases by up to 85% (Marsden 2017). This supports 
treatment initiation as soon as possible after OD. The literature also supports a clear benefit of 
higher-dose MAT medications in patients at risk for opioid OD (Dupouy 2017, Marsden 2017, 
Sordo 2017). As noted above, SUBLOCADE at 300 mg administered subcutaneously on a 
monthly dosing regimen produces exposures at or above 2 ng/ml consistently, reaching higher 
exposures that appeared to be associated with improved outcomes. A potential advantage of 
using SUBLOCADE compared to transmucosal buprenorphine products in the emergency 
department (ED) following treatment for an opioid OD is the rapid achievement of plasma 
concentrations of 2 ng/ml buprenorphine which are sustained over the dosing interval. The risks 
associated with SUBLOCADE administered to patients with OUD in the ED are minimal, 
largely related to injection site reactions, precipitated withdrawal, or sedation which are 
significantly less than risk of repeat OD in this patient population. 
 
Because there is a risk of sedation in patients who are not tolerant to opioid effects, patients who 
have a COWS of <8 and who were released from a controlled environment within the past 30 
days will be observed for 2 hours after SUBLOCADE 300 mg administration and discharged 
with a RASS score > 0. This modification is intended to allow for enrolment of populations (i.e. 
patients who were recently incarcerated) that are especially vulnerable to opioid overdose due to 
a loss of opioid tolerance. Studies have shown that opioid overdoses are the leading cause of 
death in former prisoners in the immediate post-release period (Binswanger et al 2013).  
 

 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary 
The primary objective of this study is: 
• Determine the effect of SUBLOCADE treatment after opioid OD when administered in 
the ED setting, inpatient unit or within 7 days (168 h) of overdose in clinic on repeat OD 
and death compared to a historical control group and concurrent controls who decline 
treatment participation.  
2.2 
Secondary 
The key secondary objective of this study is:  
• Determine effect of SUBLOCADE when administered in the ED setting, inpatient unit or 
within 7 days (168 h) of overdose in clinic on treatment engagement at 3 months and 6 
months comparing patients who have primarily intravenous to non-intravenous opioid 
use.  
2.3 
Exploratory 
The exploratory objectives of this study are:  
• To determine the effect of SUBLOCADE administered in the ED, inpatient unit or in the 
clinic within 7 days (168 h) of an opioid OD followed by SUBLOCADE administration 
monthly on the amount of opioid craving.  
• To determine the efficacy of SUBLOCADE administered in the ED, inpatient unit or in 
the clinic within 7 days (168 h) of an opioid OD followed by SUBLOCADE in the clinic 
on opioid use as determined by Urine Drug Screen (UDS).  
• To evaluate the effect of SUBLOCADE administered in the ED, inpatient unit or in the 
clinic within 7 days (168 h) of  an opioid OD followed by SUBLOCADE in the clinic in 
the clinic on decision making using a delay discounting task and a brief opioid demand 
measure to measure craving valuation (hypothetical maximum price participants would 
be willing to pay for access to opioid, assessing craving/valuation).  
• To evaluate the association between participant genetic polymorphisms and subjects with 
history of OD in subjects that consent to the PGx sub-study. 
• To evaluate the relationship between genetics/behavioural laboratory measures of 
decision making and treatment outcome, including repeat OD in subjects that consent to 
the PGx sub-study.  
• To determine the relationship between decision making and treatment retention and illicit 
opioid use. 
• To evaluate healthcare resource utilisation associated with either treatment regimen as 
compared to the controls (2015-to end of data collection period) obtained from VCU 
anonymized health records.   
• To assess the impact SUBLOCADE administered in the ED, inpatient unit or in the clinic 
within 7 days (168 h) of  an opioid OD followed by administration of SUBLOCADE in 

 
 
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the clinic on treatment effectiveness as measured by Treatment Effectiveness Assessment 
(TEA), on medication satisfaction as measured by the Medication Satisfaction 
Questionnaire (MSQ), and on employment, presentism and absenteeism as assessed by 
the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP). 

 
 
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3 
STUDY ENDPOINTS 
3.1 
Primary 
The primary endpoint of this study is: 
• Time to repeat OD or opioid-related death. Repeat OD or opioid-related death will be 
measured from electronic medical records and state death registries.  
• Additional comparisons on repeat OD and death rates will be made to concurrent patients 
who decline to participate in the SUBLOCADE injection. 
3.2 
Secondary 
The key secondary endpoints of the study are:  
• Numbers and percent of patients in buprenorphine treatment at 3 and 6 months after 
opioid OD comparing patients who have primarily intravenous to non-intravenous opioid 
use. 
3.3 
Exploratory 
The exploratory endpoints of this study are: 
• Opioid craving in subjects as measured by Craving Visual Analog Scale (VAS) scores. 
• Illicit opioid use as measured by urine drug screen (UDS) results. 
• Genetic predictors of treatment response and OD. 
• Predictability of treatment response based on impulse control as measured by decision 
making in the delay discounting task, and opioid cravings/valuation as measured by the 
brief opioid demand task. 
• Numbers of ED and hospital visits compared to the historical control (2015-2018) 
obtained from VCU anonymized health records.   
• Scores on Treatment Effectiveness Assessment (TEA), medication satisfaction as 
measured by the Medication Satisfaction Questionnaire (MSQ), and employment, 
presentism and absenteeism as assessed by the Work Productivity and Activity 
Impairment Questionnaire: Specific Health Problem (WPAI:SHP). 
3.4 
Safety Assessments 
Safety assessments include the proportion of subjects with AEs of the following types at any 
time during the treatment period: at least one AE, a drug-related AE, an SAE, a serious and drug-
related AE, or an AE leading to treatment discontinuation. 
Additional safety assessments include laboratory assessments, brief physical examinations, vital 
signs and concomitant medications. 

 
 
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3.5 
Health Economics and Outcomes Assessments 
Health economics and outcomes assessments include the Healthcare Resource Utilization 
questionnaire (HCRUQ, the Treatment Effectiveness Assessment (TEA), the Medication 
Satisfaction Questionnaire (MSQ), and the Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem (WPAI-SHP). 
3.6 
Hypothesis and Treatment Comparisons 
Participants who receive SUBLOCADE treatment regimen will have lower repeat OD and death 
rates compared to controls from electronic health record data. Prospective rates of OD will be 
based on ED data, self-report data, and Virginia death registry data.  

 
 
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4 
STUDY PLAN 
4.1 
Study Design 
4.2 
Duration of Treatment 
The total duration of study participation will be approximately 7 months. Subjects will be treated 
for 6 months with an End of Treatment (EOT) visit at 7 months. 
Safety follow-up telephone calls will occur 30 days after the EOT Visit if the subject is 
continuing in treatment, with an additional 5 monthly phone calls (6 months total) if the subject 
is not continuing in MAT.  
 

 
 
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5 
STUDY POPULATION SELECTION 
5.1 
Number of Subjects 
Approximately 100 subjects will be enrolled. 
5.2 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1. Signed the informed consent form (ICF) and have the ability to comply with the requirements 
and restrictions listed therein. 
2. Age: ≥ 18 years at time of executing the ICF.  
3. Currently meets DSM-5 criteria for moderate to severe OUD. 
4. Is clinically stable (respiratory rate [RR] ≥ 12, pulse oximetry > 95%, Glasgow Coma Scale 
[GCS] score of 15) and suitable for the trial in investigator’s or designee’s judgement.  
5. Agrees not to take any buprenorphine products other than those administered during the 
current study throughout participation in the study.  
6. Negative urine pregnancy test for females.  
7. Vital signs (BP, HR, temperature) considered within normal limits or non-clinically 
significant elevation, as assessed by treating physician.  
5.3 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 
1. Current diagnosis, other than OUD, requiring chronic opioid treatment. 
2. Active suicidal ideation in opinion of the Investigator or designee. 
3. Female subject that is lactating, pregnant or planning to become pregnant during their 
participation in the study. 
4. Uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social 
situations that would limit compliance with study requirements or compromise the ability of 
the subject to provide written informed consent, signs of opioid toxicity more than 2 hours 
from naloxone administration or subjects with evidence of pulmonary edema. 
5. Known allergy or hypersensitivity to SUBOXONE. 
6. Any condition that, in the opinion of the Investigator would interfere with interpretation of 
subject safety or study results. 

 
 
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7. Currently receiving MAT for OUD (e.g. methadone, buprenorphine) or received methadone 
as a treatment for OUD within 30 days prior to consent.  
8. Concurrent treatment with another investigational agent. 
9. Concurrent enrolment in another clinical study, or observational study that includes MAT. 
10. Treatment for OUD required by court order. 
11. Current or pending incarceration/ legal action that could affect participation or compliance in 
the study. 
12. Subjects who are unable, in the opinion of the Investigator, to comply fully with the study 
requirements. 
13. Less than 48-72 hours since last use of long acting opioids (e.g., methadone), by self-report.   
14. Current intoxication with benzodiazepines or alcohol.  
15. Meet current DSM-5 diagnosis for severe Benzodiazepine or Alcohol Use Disorder, 
or endorse benzodiazepine or alcohol withdrawal symptoms. 
16. Current illicit opioid users who endorse regular use of long acting opioids (e.g. methadone).  
17. Total bilirubin ≥ 1.5x the upper limit of normal (ULN), alanine aminotransferase (ALT) 
≥3xULN, aspartate aminotransferase (AST) ≥ 3xULN, serum creatinine > 2xULN, 
international normalized ratio (INR) >1.5xULN   
18. Patients with a history of Long QT Syndrome or an immediate family member with this 
condition or those taking Class lA antiarrhythmic medications (e.g., quinidine, procainamide, 
disopyramide) or Class Ill antiarrhythmic medications (e.g., sotalol, amiodarone) or other 
medications that prolong the QT interval. 
5.4 
Initial SUBLOCADE Dosing Criteria 
In order to initiate SUBLOCADE dosing the following criteria must be met: 
1) Clinically stable (respiratory rate [RR] ≥12, pulse oximetry > 95%, Glasgow Coma Scale 
[GCS] score of 15  
2) No allergic reaction or hypersensitivity to SUBOXONE sublingual film.  
 
3) More than 8 hours after the last dose of short acting opioid other than the SUBOXONE dose 
administered in the ED or at the clinic, or more than 48-72 after last dose of methadone. 

 
 
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6 
STUDY CONDUCT 
6.1 
Subject Enrolment 
Study participation begins once written informed consent is obtained; a subject ID is then 
assigned. The subject ID will be used to identify the subject during the screening process and 
throughout study participation, if applicable. 
The Investigator is responsible for maintaining a master list (i.e., a subject identification list) of 
all consented subjects and will document all subjects that did not meet study eligibility criteria 
(i.e., screen failures), including reason(s) for ineligibility (i.e., a subject screening and enrolment 
log). Ineligible subjects, as defined by the protocol-specific inclusion and exclusion criteria, 
should not receive SUBLOCADE and should be documented as screen failures.  
Controls will be selected from OD ED VCU visits beginning in 2015. The dataset will be 
anonymized; therefore, consent is not required and will not be obtained.  
6.2 
Screen Failure 
A subject will be considered a screen failure if written informed consent is obtained but he/she 
does not meet inclusion / exclusion criteria or does not receive SUBLOCADE for another reason 
(example: the subject leaves prior to administration).  
Subjects that screen fail may be re-screened for participation in the trial if they return to the ED, 
inpatient unit or outpatient treatment facility after a subsequent OD.  
6.3 
Subject Completion 
6.3.1 
Treatment Completion 
Subjects that complete the EOT visit will be considered treatment completers.  
6.4 
Withdrawal and Stopping Criteria 
6.4.1 
Subject Withdrawal from Treatment 
A subject will be considered withdrawn from treatment if the subject has permanently 
discontinued study treatment. The primary reason for withdrawal from treatment must be entered 
into the electronic case report form (eCRF) (e.g., death, AE, protocol non-compliance, 
investigator’s decision, or as requested by the subject for another or unknown reason). Subjects 
who discontinue study treatment for any reason other than lost to follow-up will continue to be 
followed on an approximately monthly basis by telephone for repeat OD and treatment status and 
any scheduled HEOR assessments through to the end of their scheduled 30-day safety follow up 
telephone call.  
Subjects who are withdrawn from the study for any reason after treatment with SUBLOCADE 
will not be replaced. 

 
 
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6.4.2 
Subject Withdrawal from the Study 
If the subject has permanently discontinued study treatment and monthly follow-up calls, he/she 
will be considered withdrawn from the study. The primary reason for withdrawing from the 
study must be entered into the eCRF (e.g., subject is lost to follow-up, or investigator’s 
discretion).  
Female subjects with confirmed pregnancies will be withdrawn from the study. See Protocol 
Section 12.2 for additional information.   
6.4.3 
Subject Withdrawal of Consent 
If a subject withdraws consent, the primary reason should be entered into the eCRF. The subject 
will not receive any additional doses of study treatment. However, the subject may be offered 
additional tests as needed to monitor their safety (e.g., EOT safety assessments or procedures).   
6.4.4 
Subjects Lost to Follow-up 
In cases of a missed visit, the Investigator or designee must attempt to contact the subject and re-
schedule as soon as possible. The Investigator or designee must counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether or not the subject 
wishes to and/or should continue in the study.  
In the event a subject misses 5 consecutive weeks’ worth of visits, they will be considered to 
have ceased treatment and withdrawn from the study. Investigators or designees must make a 
reasonable effort to contact the subject. Two documented attempts (e.g., phone, email, etc.) to 
contact the subject followed by a certified mailed letter is considered reasonable. Subjects who 
can no longer be contacted will be considered lost to follow-up. 
For the purpose of documenting date of discontinuation for a subject confirmed to be lost to 
follow-up, the date of discontinuation will be the date of last in-person visit.   
6.4.5 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping criteria 1-5 are defined below: 
1. The subject has ALT or AST >3 x ULN and bilirubin >2 x ULN (˃35% direct bilirubin) (or 
ALT or AST >3 x ULN and international normalized ratio (INR) ˃1.5, if INR measured). 
Note: if serum bilirubin fractionation is not immediately available, withdraw study drug for 
that subject if ALT or AST >3 x ULN and bilirubin >2 x ULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, the presence of 
detectable urinary bilirubin on dipstick should be recorded, indicating direct bilirubin 
elevations and suggesting liver injury. 
2. The subject has ALT or AST >8 x ULN. 
3. The subject has ALT or AST >5 x ULN but <8 x ULN persisting for > 2 weeks. 

 
 
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4. The subject has ALT or AST >3 x ULN if associated with symptoms (new or worsening) 
believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
5. The subject has ALT or AST >5 x ULN but <8 x ULN and cannot be monitored weekly for 
>2 weeks. 
6.4.5.1 
Study Treatment Re-challenge 
Study treatment re-challenge after liver chemistry stopping criteria are met by any study subject 
is not allowed. If clinically indicated, the SUBLOCADE depot may be surgically removed 
within 14 days of the injection. 

 
 
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7 
STUDY SUSPENSION OR TERMINATION 
In cases where a trial is suspended or terminated for safety reasons, the Principal Investigator 
(PI) will promptly inform the Regulatory Authorities of this action and the reason(s) for the 
suspension or termination.  
If required by applicable regulations, the PI must inform the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) promptly and provide the reason(s) for the 
suspension or termination.  

 
 
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8 
DESCRIPTION OF STUDY PROCEDURES 
Study assessments and procedures, including the timing of assessments, are summarized in 
Appendix 1 and Appendix 2. Further details on efficacy assessments are provided in Section 8.6.  
A signed written informed consent form must be obtained from the subject before any study 
assessments or procedures may be performed. At screening, if an assessment or procedure has 
already been performed as part of routine standard of care and was completed within the 
protocol-specific screening window, the assessment or procedure does not need to be repeated, 
unless clinically indicated. All assessments and procedures may be performed more frequently, if 
clinically indicated. 
8.1 
Demographics and Medical History 
A detailed medical history will be obtained during the screening period. This will include 
information regarding the subject's complete history of relevant medical conditions, diagnoses, 
procedures, treatments, detailed history of drug use and any other noteworthy medical 
information. Any updates to medical history information made available during the course of the 
study will be captured. 
8.1.1 
DSM-5 Checklist for OUD, AUD and SUD and Mini-International 
Neuropsychiatric Interview (DSM 5 version) 
At screening, the DSM-5 Checklist will be performed to assess for the presence and severity of 
OUD, AUD and SUD and will be reviewed by the PI or Sub-Investigator. At visit 2, the 
standardized diagnostic tool of the Mini-International Neuropsychiatric Interview (M.I.N.I), 
DSM-5 version (7.0.2) (Sheehan, 2016) will be used to screen for other DSM-5 substance-use 
disorders or other psychiatric co-morbidities.   
8.2 
Physical Examination 
A brief physical examination will include an assessment of general appearance, lungs and 
cardiovascular system. The brief physical examination will occur in the ED, inpatient unit or at 
the clinic within 7 days (168 h) of the opioid OD at screening, and at the first clinic visit. 
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 endpoint.   
 
The Richmond Agitation-Sedation Scale (RASS) will be utilized to assess sedative effects of 
SUBLOCADE 300 mg in patients with COWS <8 and who were released from a controlled 
environment in the past 30 days (Sessler et al 2002). Patients with a RASS score > 0 will be 
eligible for discharge after a 2 hour wait period.  
8.3 
Vital Signs 
Evaluation of vital signs will occur after the subject has been in a sitting position for ≥3 minutes 
and comprises systolic and diastolic blood pressure, pulse rate, respiratory rate, oxygen 

 
 
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saturation measurement and oral temperature. Any clinically significant vital sign measurements 
(as determine by the Investigator or a medically qualified designee) will be recorded as an AE 
and re-assessed at medically appropriate intervals until the value returns to an acceptable range, a 
specific diagnosis is established, or the condition is otherwise explained. 
Vital signs will be recorded in the source document and the eCRF per the Schedule of Events 
(Appendix 1 and Appendix 2). 
8.4 
Treatment of Precipitated Withdrawal 
Subjects experiencing precipitated withdrawal, may be treated symptomatically (SAMHSA TIP 
63 2018): 
• 
nausea: ondansetron or metoclopramide 
• 
diarrhea: loperamide 
• 
insomnia: diphenhydramine  
• 
pain: nonsteroidal anti-inflammatory drugs 
8.5 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed at the time points listed in the Schedule of Events 
(Appendix 1 and Appendix 2) in a licensed clinical laboratory. Urine pregnancy tests and urine 
drug screens may be performed using a licensed point of care test (dipstick). Abnormal liver 
function tests (LFTs) will be followed at clinic visits according to investigator’s judgement. An 
etiological evaluation will be performed if a hepatic adverse event (AE) is suspected. 
Subjects are to be in a seated or supine position during blood collection.  
The following clinical laboratory tests specified in Table 1will be performed. 
 
 
 

 
 
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Table 1 
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 3-part differential 
 
Pregnancy: 
Urine Pregnancy (only for females not 
postmenopausal or surgically sterile for at least 1 
year) 
 
Additional Tests:  
HIV 
HCV B/C  
Urine Drug Screen (UDS):  
Opioids 
Fentanyl  
Buprenorphine 
Methadone 
Oxycodone 
Amphetamines 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Cocaine 
Methamphetamines 
Phencyclidine 
 
Breath alcohol test 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Calculated creatinine clearance 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase and subtypes 
Gamma-glutamyl transferase 
Globulin 
Glucose (non-fasting) 
Lactate dehydrogenase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
 
HIV = human immunodeficiency virus antibodies; HCB = Hepatitis B Virus; HCV = Hepatitis C virus. 
 

 
 
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8.5.1 
Sample Collection, Storage, and Shipping 
Samples will be analysed locally by an approved laboratory. 
8.6 
Efficacy Assessments 
The primary measures of efficacy will be repeat OD and death data. Secondary measures will 
include treatment entry and retention. Additionally, results from Urine Drug Screening (UDS) 
and the Opioid Craving Visual Analogue Scale (OC-VAS) will be reviewed as exploratory 
measures.  
8.6.1 
Urine Drug Screen 
Urine drug screening will be collected at every visit starting at Week 1 Day 2 as outlined in the 
Schedule of Events (Appendix 2).  
8.6.2 
Opioid Craving Visual Analog Scale (OC-VAS) 
The OC-VAS is an instrument that measures a characteristic or attitude that is believed to range 
across a continuum of values and cannot easily be directly measured. The amount of opioid 
craving that a subject feels for illicit opioids (not the buprenorphine used for treatment of OUD) 
can be recorded along a continuum from “no craving at all” to “strongest craving ever” 
(McMillan, 1996). Operationally, the OC-VAS is a horizontal line, 100 millimetres (mm) in 
length, anchored by word descriptors at each end. The subject indicates the point on the line that 
he/she feels represents his/her perception of their current state. The OC-VAS score is the 
difference from the left hand end of the line to the point that the subject marks. The OC-VAS 
will be performed before the SUBOXONE sublingual film test dose, before and after the 
SUBLOCADE injection and at each subsequent scheduled clinic visit as outlined in the Schedule 
of Events (Appendix 1 and Appendix 2).  
8.7 
Supportive Assessments 
8.7.1 
Delay Discounting Task 
The delay discounting task is a hypothetical assessment of delay discounting (Koffarnus 2014) in 
which subjects choose between receiving a small amount of money immediately (e.g, $50 now) 
and a larger amount of money after a delay (e.g., $100 in 1 month). This task will be 
administered electronically as outlined in the Schedule of Events (Appendix 1 and Appendix 2).  
8.7.2 
Opioid Demand Task 
Participants will complete a brief, hypothetical assessment of opioid craving/valuation in which 
they report the maximum amount of money they would pay to receive a dose of their preferred 
opioid drug. This task will be administered electronically as outlined in the Schedule of Events 
(Appendix 1 and Appendix 2).  

 
 
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8.7.3 
Clinical Opiate Withdrawal Scale (COWS) 
The COWS is an 11-item, validated instrument used to assess signs and symptoms of opiate 
withdrawal (Wesson 2003, Tompkins 2009). The score is the sum of the response to each of the 
11 items and ranges from 0 to 48. A score of 5 to 12 is considered mild, 13 to 24 is moderate, 25 
to 36 is moderately severe, and a score > 36 is considered severe withdrawal. The COWS will be 
assessed by a qualified and trained individual throughout the course of the study. The COWS 
will be administered electronically and will be performed before the SUBOXONE sublingual 
film test dose, before and after the SUBLOCADE injection and at each subsequent scheduled 
clinic visit, as outlined in the Schedule of Events (Appendix 1).   
8.8 
Pharmacogenomic Assessment 
Buccal swab samples for PGx analyses will be obtained following informed consent from the 
subject to participate in the optional PGx sub-study. No analyses, including genotyping and 
DNA sequencing, will be performed for personal identification. All samples will be identified by 
subject number and will not include any subject personal identifiers. The PGx samples are for 
genotyping. In the future, protein, RNA, metabolite studies or other research may be performed. 
Pharmacogenomic sample collection, handling, and storage are explained in greater detail in the 
laboratory manual. 
8.9 
Health Economics and Outcomes Assessments 
Health economics and outcomes assessments will be collected at the time points listed in 
Appendix 1 and Appendix 2.  
8.9.1 
Treatment Effectiveness Assessment (TEA) 
The Treatment Effectiveness Assessment (TEA) (Ling 2013) elicits subject responses that help 
the subject and the clinician to quickly gauge subject progress in treatment and in recovery. This 
progress is determined according to the subject’s sense of what is important within four domains 
established by prior research. Improvement in each of the four recovery-oriented domains 
(substance use, health, lifestyle, and community) can be assigned a value of 1 (not improved or 
little improved) to 10 (very much improved) by the subject. The total score of improvement since 
treatment start is the sum of the responses to the four TEA domains, ranging from 4 (no 
measurable improvement or worse) to 40 (significantly improved). Subjects provide both 
numerical responses and representative details on their substance use, health, lifestyle, and 
community. In other words, the TEA assesses treatment progress and recovery, based on the 
subject’s perspective.  
8.9.2 
Healthcare Resource Utilization Questionnaire (HCRUQ) 
The HCRUQ will be completed by the Investigator or qualified designee and will collect 
hospitalizations; residential substance abuse treatment; general practitioner, specialist, and 
counselling visits; and Emergency Department (ED) visits.  Also, The HCRUQ information will 
be obtained from informatics and electronic medical records from the respective site. It will 

 
 
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include information on medical services provided in the inpatient, outpatient, emergency 
department and other ancillary services available within the site’s network. 
8.9.3 
Medication Satisfaction Questionnaire 
The MSQ is a single-item questionnaire that evaluates satisfaction with medication 
(Vernon 2010). It is a subject-completed instrument with the following response levels. 
Responses are ordinal but can also be categorized into satisfied (5-7), neutral (4), or dissatisfied 
(1-3). The MSQ has shown an acceptable reliability (ICC>0.80) and validity (known groups, 
convergent and divergent validity) based on a randomized controlled trial with 191 schizophrenia 
patients (Vernon 2010).  
8.9.4 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem (WPAI: SHP) 
The impact of the disease and its treatment on work productivity and regular daily activities will 
be assessed by the WPAI Questionnaire (Reilly 1993). The WPAI questionnaire has 2 versions: 
WPAI-general health (WPAI-GH) and WPAI-Specific Health Problem (WPAI- SHP).  In this 
study, WPAI-SHP will be used to target the measure to OUD. The WPAI-SHP has 6 items 
designed to measure employment, number of hours missed from work, and activity impairment 
during the past seven days due to the health problem. WPAI: SHP has been used among patients 
with OUD (Hoffman 2017).  
8.10 Appropriateness of Measurements 
The instruments used (e.g. COWS, OC-VAS, delay discounting task, opioid demand) were 
developed to measure the specific symptoms and or characteristics exhibited by individuals with 
opioid-dependence.  
8.11 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or ICH/GCP 
requirements. The noncompliance may be either on the part of the subject, the Investigator, or 
the study site staff. It is the responsibility of the Investigator and study site staff to use 
continuous vigilance to identify and report deviations to the IRB/IEC. All deviations must be 
addressed in the study source documents. Protocol deviations must be sent to the local IRB/IEC 
as required. The Investigator and study site staff are responsible for knowing and adhering to the 
IRB/IEC’s requirements.  

 
 
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9 
STUDY DRUG MANAGEMENT 
9.1 
Description  
The term ‘study treatment’ is used throughout the protocol to describe any combination of 
product received by the subject as per the protocol design. Study treatment may therefore refer to 
the individual study treatments or the combination of those study treatments. 
9.1.1 
Study Treatments 
9.1.2 
SUBLOCADE 
SUBLOCADE injection is a colorless to amber sterile solution for SC injection designed to 
deliver buprenorphine at doses of 100 mg or 300 mg at a controlled rate over a one-month 
period. The active ingredient in SUBLOCADE injection is buprenorphine free base, a mu-opioid 
receptor partial agonist and a kappa-opioid receptor antagonist. Buprenorphine is dissolved in 
ATRIGEL at 18% by weight and is a biodegradable 50:50 poly (DL-lactide-co-glycolide) 
polymer and a biocompatible solvent, N-methyl-2-pyrrolidone (NMP). Refer to the IB or 
prescribing information for additional information on the physical and chemical properties of the 
drug substance and for a list of excipients. 
Adequate precautions must be taken to avoid direct contact with the product. Occupational 
hazards and recommended handling procedures are provided in the prescribing information. 
9.1.3 
SUBOXONE Sublingual Film 
SUBOXONE sublingual film is an orange rectangular film with a white printed logo. Each 
SUBOXONE sublingual film contains buprenorphine HCl and naloxone HCl dihydrate at a 4:1 
ratio expressed as the free bases. Films are intended for sublingual or buccal administration and 
are available in 4 dosage strengths (2 mg/0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg). 
Refer to the SUBOXONE Sublingual Film USPI for additional information on the physical and 
chemical properties of the drug substance and for a list of excipients. 
SUBOXONE sublingual film is commercially available and will be obtained by VCU Health 
System Pharmacy.  
9.1.4 
Blinding 
This is an open-label trial with no blinding.  
9.2 
Packaging and Storage 
SUBLOCADE study labels will be developed in accordance with GMP and local regulatory 
requirements. SUBLOCADE will be individually numbered.  
SUBLOCADE injection is supplied as a prefilled syringe. SUBLOCADE will be packaged and 
labelled in a manner consistent with the study design and applicable regulations.  The packaging 
includes an outer carton with an inner pouch which contains the pre-filled syringe, oxygen absorber 
and a sterile 19-gauge, 5/8-inch hypodermic safety needle.   

 
 
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SUBLOCADE should be stored in a secure location in accordance with federal, state and local 
requirements for storage of Schedule III Controlled Substance under refrigerated conditions 
between 2ºC to 8ºC (36°F to 46°F). Once outside the refrigerator, SUBLOCADE may be stored in 
its original packaging at room temperature (15°C to 30°C, [59°F to 86°F]), for up to 7 days prior 
to administration. Discard SUBLOCADE if left at room temperature for longer than 7 days.  
Study treatment must be handled strictly in accordance with the protocol and applicable local 
laws and regulations. 
 
SUBOXONE sublingual film is an orange rectangular sublingual film with a white printed logo. 
SUBOXONE is supplied in boxes of 30 count film strips. SUBOXONE sublingual films should 
be stored at 25°C (77°F) with excursions permitted between 15-30°C (59-86°F).   
 
9.3 
Drug Administration 
9.3.1 
SUBLOCADE Injection 
SUBLOCADE injection will be administered following confirmation that the subject meets all 
eligibility and continuation criteria. The designated study treatment should be administered under 
the supervision of the Investigator, a suitably qualified member of the study team, or by a 
pharmacist. The Investigator or designee agrees not to administer SUBLOCADE from, or store 
it, at any location other than the study site agreed upon with the Indivior. Detailed instructions 
related to preparation of SUBLOCADE injection are outlined in the Prescribing Information.   
SUBLOCADE subcutaneous (SC) injection sites should be rotated (see USPI for details) and the 
product must not be administered intravenously or intramuscularly. Eligible subjects will receive 
up to 7 subcutaneous injections of SUBLOCADE injection as outlined in the SOE (Appendix 1 
and Appendix 2). No injections are permitted outside of the protocol-specified window without 
the approval of the PI. Detailed instructions regarding the administration of SUBLOCADE 
injections are located in the USPI.  
Time of dose is defined as the time the SUBLOCADE SC injection is complete. The time of 
dose and any dosing observations (e.g., partial doses or other issues with the injection) will be 
recorded in the source documentation; in addition, time of dose will be recorded in the eCRF.  
The Investigator will not supply SUBLOCADE injection to any person except study personnel 
for SC injection of subjects in this study.   
Adequate precautions must be taken to avoid direct contact with SUBLOCADE injection. 
Occupational hazards and recommended handling procedures are provided in the SUBLOCADE 
USPI.  
9.3.2 
SUBOXONE Sublingual Film 
On Day 1, SUBOXONE sublingual film (4 mg/1 mg) will be administered in the ED, inpatient 
unit or at the clinic within 7 days of the opioid overdose event.  

 
 
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SUBOXONE sublingual film can be administered by the sublingual or buccal routes. Sublingual 
Administration: Place one film under the tongue, close to the base on the left or right side and 
allow to completely dissolve. Buccal Administration: place one film on the inside of the left or 
right cheek and allow to completely dissolve. For more information on SUBOXONE sublingual 
film administration, refer to the prescribing information.  
9.4 
Accountability 
The Investigator is responsible for ensuring that SUBLOCADE received at the site is 
inventoried, accounted for and documented in accurate study treatment accountability records 
and filed in the eCRF. A record of the number of SUBLOCADE injections and associated lot 
and kit number administered to each subject must be maintained and reconciled with the eCRF. 
Unused SUBLOCADE injection will be destroyed on-site and documented per VCU health 
guidelines. 
A record of the SUBOXONE sublingual film test dosage and time of administration will be 
recorded in the source. 
9.5 
Reporting Product Complaints 
The Investigator and study site staff are responsible for prompt recognition and reporting of 
product quality complaints to Indivior. A product complaint is any concern pertaining to the 
manufacturing or quality control of the product and includes, but is not limited to, the quality and 
quantity of a drug product, labelling defects, missing inserts, packaging defects or difficult to 
open packaging, product that is thought to be ineffective, or has an appearance, taste or odour 
that is outside of what is expected.  
All product complaints should be reported to Indivior within one (1) business day after 
identifying the issue using the following email address: R&DQA@indivior.com and provide 
the following information: 
• PI Name 
• Site contact/reported by 
• Product description including unit or kit number for individually numbered units. 
• Subject Number (if already assigned to a subject) 
• Description of issue 
• Picture, if available (photographs should be taken only if safe to do so/within site policy or 
practice to take photograph) 
If the product has not yet been opened (i.e. product does not pose any hazard), retain the product 
and packaging in a quarantined space until further instruction is provided by Indivior. If the 
product is potentially hazardous, dispose per site process and document in the source.  

 
 
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9.6 
Concomitant Therapies 
Concomitant medications will be collected from screening until the EOS visit at the time points 
listed in the SOE (Appendix 1 and Appendix 2). Any concomitant medications (including herbal 
preparations) taken during the study will be recorded in the source documents and in the eCRF. 
Any changes in concomitant therapy during the study will be documented, including cessation of 
therapy, initiation of therapy and dose changes. 
9.6.1 
Permitted Concomitant Therapies 
The Investigator may prescribe concomitant medications or treatments deemed necessary to the 
subject, with the exception of those medications defined in Section 9.6.3 of the protocol.  
9.6.2 
Drug-Drug Interactions 
Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS 
depressants, including alcohol, increases the risk of respiratory depression, profound sedation, 
coma, and death.  
The SUBLOCADE prescribing information should be referenced regarding use of the below 
concomitant therapies.  
• Benzodiazepines and Other Central Nervous System (CNS) Depressants 
• Cytochrome P450 3A4 Inhibitors 
• Cytochrome P450 3A4 Inducers 
• Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 
• Antiretrovirals: Protease Inhibitors (PIs) 
• Serotonergic Drugs 
• Monoamine Oxidase Inhibitors (MAOIs) 
• Muscle Relaxants 
• Diuretics 
• Anticholinergic Drugs 
9.6.3 
Prohibited Concomitant Therapies 
Subjects should be instructed not to take any medications, including over-the-counter products, 
without first discussing with the Investigator.  
Concomitant use of buprenorphine or methadone is prohibited.  

 
 
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9.7 
Compliance 
SUBOXONE sublingual film will be administered in the ED, inpatient unit or at the clinic within 
7 days (168 hours) of opioid OD and documented in the source and recorded in the eCRF.  
SUBLOCADE will be administered by licensed healthcare provider, delegated by the 
Investigator, in the ED and out-patient as delegated by the Investigator. Injection sites will be 
assessed for evidence of attempted removal of the depot by the subject. The assessment and any 
findings will be documented in the source and recorded in the eCRF. Likewise, surgical removal 
by a physician will be documented in the source and recorded in the eCRF.  
Use of prohibited concomitant medications will be evaluated per the Concomitant Medication 
assessment outlined in the Schedule of Events (Appendix 1 and Appendix 2), documented in the 
source and recorded in the eCRF. 

 
 
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10 ADVERSE EVENTS 
The Investigator or designee is responsible for identifying, documenting and reporting events 
that meet the definition of an AE.   
An AE is any untoward medical occurrence in a subject associated with the use of an IMP 
regardless of the presence of a causal relationship to the IMP. An AE can be any unfavourable 
and unintended sign (including an abnormal laboratory finding) symptom or disease (new or 
exacerbated) temporally associated with an IMP, whether or not considered related to the IMP. 
Events meeting the definition of an AE include: 
• New condition detected after IMP administration even though the AE may have been present 
prior to receiving IMP. 
• Exacerbation of a pre-existing condition (including intensification of a condition and/or an 
increase in frequency). 
• Any abnormal laboratory test results or other safety assessments felt to be clinically 
significant in the opinion of the Investigator (including those that worsen from baseline).  
• Symptoms and/or the clinical sequelae of a suspected interaction or an OD of either IMP or a 
concomitant medication. 
• Signs, symptoms or the clinical sequelae resulting from special interest conditions (e.g.,  
medication error, IMP withdrawal, injection site tampering resulting in removal of the depot 
etc.). Overdose per se will not be reported as an AE/SAE unless this is an intentional OD 
taken with possible suicidal/self-harming intent. This should be reported regardless of 
sequelae. 
• Symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they 
fulfil the definition of an AE. 
• Symptoms and/or clinical sequelae that resulted in intervention. 
Events that do not meet the definition of an AE include: 
• The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease being studied, unless more severe than expected for the subject’s condition. 
• Medical or surgical procedures; the condition that leads to the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital, hospitalization for elective surgery, hospitalization for 
observation in the absence of an AE). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 

 
 
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10.1 Assessment of Adverse Events 
The Investigator is ultimately responsible for assessing and reporting all Aes as outlined in the 
protocol. The assessment and reporting of Aes may be delegated to a medically qualified sub-
investigator, trained on this study protocol, who is listed on the delegation of authority log. All 
Aes regardless of treatment group or suspected causal relationship to the IMP will be reported as 
described in this protocol.   
Adverse events should be volunteered by the subject or solicited from the subject using a 
standard statement, obtained from examination of the subject at a site visit, or from observations 
of clinically significant laboratory values or special examination abnormal values. If an event 
assessed by one of the study scales requires intervention, or if in the opinion of the Investigator, 
it is clinically significant, then it will be reported as an AE. 
All Aes are to be assessed and recorded in a timely manner and followed to resolution or until 
the Investigator determines that there is not an anticipated resolution. Each AE is to be 
documented with reference to 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 IMP-related or not. 
10.1.1 
Time Period for Collecting Adverse Events 
Adverse events will be collected from the time of signed informed consent until completion of 
the EOT visit. SAEs will be reported through the end of the safety follow-up period. 
Ongoing SAEs at the safety follow-up phone call that, in the opinion of the Investigator, are 
associated with the IMP, will be followed and reported as described in Section 11.2.   
All SAEs that, in the opinion of the Investigator, are associated with the IMP will be followed to 
resolution.  
In the event a subject misses 5 consecutive weeks’ worth of visits, they will be considered to 
have ceased treatment and withdrawn from the study. Investigators or designees must make a 
reasonable effort to contact the subject. Two documented attempts (e.g., phone, email, etc.) to 
contact the subject followed by a certified mailed letter is considered reasonable. Subjects who 
can no longer be contacted will be considered lost to follow-up. 
10.1.2 
Assessment of Intensity 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as “serious,” which is based on 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. 
 

 
 
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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.   
Adverse events with changes in severity should be documented as separate events. 
10.1.3 
Assessment of Causality 
The Investigator or a medically qualified sub-investigator, trained on this study protocol, listed 
on the delegation of authority log is responsible for determining the AE relationship to the 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 IMP and cannot be reasonably 
explained by other factors (e.g., the subject’s clinical state, concomitant 
therapy, and/or other interventions). 
A “reasonable possibility” is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. The Investigator will 
use clinical judgment to determine the relationship. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors and the temporal relationship of 
the event to the IMP will be considered and investigated. The Investigator will also consult the 
IB and/or USPI, for marketed products, in the determination of his/her assessment. For each 
AE/SAE the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
There may be situations when an SAE has occurred and the Investigator has minimal information 
to include in the initial report. However, it is imperative that the Investigator always make an 
assessment of causality for every event prior to the initial transmission of the SAE data to 
Indivior or designated representative. The Investigator may change his/her opinion of causality 
in light of follow-up information and amend the SAE data collection tool accordingly. The 
causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
10.1.4 
Clinical Laboratory Changes 
Changes in laboratory values, 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 the lab test result is associated with accompanying symptoms, and/or requires additional 
diagnostic testing or intervention (medical, surgical), and/or requires additional significant 

 
 
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treatment, and/or requires temporal or permanent discontinuation of IMP, or a change to dosing 
other than as permitted by protocol, or if considered to be clinically significant by the 
Investigator or medically qualified designee.  
Screening laboratory assessments, if determined to be clinically significant by the Investigator, 
are not Aes. 
It is noted that any liver abnormality > 3x 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 3. 
 

 
 
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11 SERIOUS ADVERSE EVENTS 
The Investigator or designee is responsible for identifying, documenting and reporting events 
that meet the definition of an SAE. 
An SAE is any event that meets any of the following criteria: 
• Death 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received SUBLOCADE 
injection 
• Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, 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. Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
 
• Potential Hy’s Law cases indicative of medication-induced hepatocellular injury, defined as: 
o ALT or AST >3x ULN and total bilirubin of >2x ULN (or INR >1.5 if measured) with no 
other reason found to explain combination of increased ALT and total bilirubin, such as 
hepatitis A, B, or C; pre-existing or acute liver disease; or another drug capable of 
causing the observed injury. Note: INR threshold does not apply to subjects receiving 
anticoagulants 
o ALT or AST >3x ULN with systemic symptoms (fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia [> 5%]) 
Potential Hy’s Law cases should be managed as described in Appendix 3.  
An AE is considered “life threatening” if the subject was at immediate risk of death from the 
event as it occurred; i.e., it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, IMP-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening even though IMP-induced 
hepatitis can be fatal. 

 
 
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Adverse events requiring hospitalization should be considered SAEs. Hospitalization for elective 
surgery or routine clinical procedures that are not the result of AE (e.g., elective surgery for a 
pre-existing condition that has not worsened) should not be considered Aes or SAEs. If anything 
untoward is reported during the procedure, that occurrence must be reported as an AE (either 
‘serious’ or ‘non-serious’) according to the usual criteria. 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or other outpatient setting. Complications that 
occur during hospitalization are Aes. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether ‘hospitalization’ occurred 
or was necessary, the AE should be considered serious. 
An AE is incapacitating or disabling if the experience results in a substantial and/or permanent 
disruption of the subject’s ability to carry out normal life functions.  
11.1 Documenting Serious Adverse Events 
When an SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory and diagnostic reports) pertaining to the event. The 
Investigator will then record all relevant information regarding an SAE on the appropriate 
electronic form in the eCRF. 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to 
Indivior in lieu of completion of the SAE Reporting Form. However, there may be cases where 
copies of medical records are requested by Indivior or designated representative. In this instance, 
all subject identifiers, with the exception of subject number, will be redacted on the copies of the 
medical records prior to submission to Indivior. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis will be documented as an AE or 
SAE and not the individual signs/symptoms. 
11.2 Reporting Serious Adverse Events 
11.2.1 
Reporting of Serious Adverse Events 
Once the Investigator determines that an event meets the protocol definition of an SAE, the SAE 
will be reported to the IRB by the Investigator (or designee) within 24 hours from first being 
aware of the event by completing the appropriate eCRF(s). Any follow-up information on a 
previously reported SAE will also be reported to the IRB within 24 hours. 
Where additional information is needed or expected, the Investigator will not wait to receive all 
information before reporting the event to the IRB. The Investigator must provide an assessment 
of causality at the time of the initial report as described in Section 10.1.3 of the protocol.  
Indivior will be informed of SAEs within 24 hours of from the Investigator first becoming aware 
of the event by using the form provided by Indivior. Any follow-up information on a previously 

 
 
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reporting SAE will be reported to Indivior within 24 hours of the Investigator becoming aware of 
the update.  
Reporting email address: PatientSafetyNA@Indivior.com  
11.2.2 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt receipt of notifications of SAEs to the IRB or designated representative from 
investigators is essential in ensuring that legal obligations and ethical responsibilities regarding 
the safety of subjects are met.  
A suspected unexpected serious adverse reaction (SUSAR) is an SAE related to the IMP 
administered in any dose and that, in its nature or severity, is inconsistent with the IB or Product 
Information for marketed products.  
11.2.3 
Overdose 
Any instance of intentional OD (whether or not it involved IMP) must be communicated as an 
SAE and fully documented. Details of any signs or symptoms and their management should be 
recorded, including details of any antidote(s) administered. 
 
11.2.4 
Depot removal 
  
Any instance of depot removal (by a clinician, or injection site tampering by the study subject 
resulting in removal of the depot) will be considered as an AE of special interest and must be 
communicated to Indivior or designated pharmacovigilance (PV) representative (email address 
for reporting: PatientSafetyNA@Indivior.com) within 24 hours of the Investigator first becoming 
aware of the event by using the SAE reporting form provided by the Indivior (seriousness criteria 
to be left unticked, if applicable). 
 

 
 
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12 PREGNANCY 
12.1 Collecting and Reporting Pregnancy Information 
All pregnancies will be collected from receipt of IMP through the scheduled 30-day follow-up 
phone call. Subjects who do not continue in MAT will have pregnancies collected until 
5 terminal half-lives following the last dose of IMP. For this IMP this period is approximately 
12 months. All confirmed pregnancies that occur within this study will be followed until 
resolution (i.e., termination [voluntary or spontaneous] or birth).  
Pregnancy of a study subject without associated unexpected or adverse sequelae is not a 
reportable AE, but must be reported to Indivior or designated PV representative (email address 
for reporting: PatientSafetyNA@Indivior.com), using the Clinical Trial Pregnancy Reporting 
Form within 24 hours of the Investigator first being aware of the pregnancy.  
The pregnancy must be followed up to determine outcome (including premature termination) and 
status of mother and infant. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date; however, additional follow-up for up to 2 years may 
be required if there are any complications for the infant. Any termination of pregnancy will be 
reported, regardless of foetal status (presence or absence of anomalies) or indication for 
procedure. 
Any pregnancy complication or elective termination for medical reasons must be reported as an 
AE or SAE. Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the Investigator as possibly 
related to the study treatment, must be promptly reported to Indivior or designated PV 
representative. While the Investigator is not obligated to actively seek this information in former 
study subjects, he or she may learn of an SAE through spontaneous reporting. 
12.2 Action to be Taken if Pregnancy Occurs in a Female Subject 
If a female subject suspects that she is pregnant (e.g., missed period, self-administered pregnancy 
test) during treatment or within 6 months after the discontinuation of SUBLOCADE, she should 
return to the clinic as soon as possible to undergo a urine pregnancy test. Subjects will receive a 
card with clinic information at the screening visit, including instructions on follow-up should 
they suspect pregnancy (follow up with the clinic or their usual place of care).  
If pregnancy is confirmed at any time during the study, the subject will be withdrawn from study 
treatment and will undergo all final study visit procedures (with the exception of any additional 
pregnancy testing) and continue with monthly telephone follow-up. Subjects who are determined 
to be pregnant will be referred to the VCU outpatient obstetrics clinic or other obstetrics clinic in 
the local vicinity if they do not wish to attend the VCU clinic.   
The Investigator should fully inform the female subject of the potential risk to the fetus as well 
as discuss the desirability of continuing the pregnancy. 
 

 
 
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13 DATA MANAGEMENT 
13.1 Data Collection and Management 
Data will be entered into the eCRF. Clinical data will be managed in accordance with the data 
management plan to ensure that the integrity of the data is maintained. Adverse events and 
medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Concomitant medications will be coded using the WHO Drug Dictionary (WHO-
DD).  
13.1.1 
Historical and Concurrent Control Data 
The historical and concurrent control data used for exploratory OD comparison analyses will be 
provided by Virginia Commonwealth University as an anonymized data extract from their 
electronic medical record system beginning in 2015. Data will include, but not be limited to; 
demographics, discharge diagnoses and status and ICD 9/10 codes.   
13.1.2 
Database Quality Assurance 
The eCRFs 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 eCRFs, and all corrections will be documented. 
13.1.3 
Source Documents  
The Investigator is responsible for the quality of the data recorded in the CRFs. The data 
recorded should be a complete and accurate account of the subject’s record collected during the 
study.  
Study data are to be gathered onto primary source documents at the clinical site, except for 
certain assessments to be captured as direct entry on a tablet as indicated in the next paragraph. 
Completion of source documents will precede the completion of the CRF. Source documents 
may be electronic, hard copy, or a combination of both and are defined as the results of original 
observations and activities of a clinical investigation. Source documents will include, but are not 
limited to, progress notes, electronic data, screening logs, and recorded data from automated 
instruments. All source documents pertaining to this study will be maintained by the Investigator 
and made available for direct inspection by the authorized study personnel outlined in the ICF. 
The CRF will be considered the source document for individual CRF elements such as study-
specific scales if those data are collected directly onto a CRF. 
The following assessments will be collected as direct data entry: 
• HCRUQ 
• COWS 
• OC-VAS 

 
 
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• Opioid Demand Task 
• Delay Discounting Task 
• HEOR assessments 

 
 
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14 STATISTICS 
14.1 General Procedures 
This section describes methods for sample size determination, analysis populations 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.  
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 the 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 the study for all subjects 
enrolled.  
14.2 Sample Size 
The study will be powered based upon the primary endpoint, repeat opioid OD and death 
compared to historical and concurrent control data.  
 
Rationale for sample size:  Power calculations: sample size was calculated based on a primary 
outcome measure of reduced repeat opioid OD rates. Previous research has shown self-reported 
repeat lifetime OD rates of 15-23% for patients who were seen for an opioid OD (Morizio, Baum 
et al. 2017).  
 
Based on VCU health system data, for patients seen in the ED for an opioid OD in 2016, 11.5% 
of those patients were either seen again in the ED for an opioid OD or had died based on 
Virginia Department of Health death registry data within 6 months after their initial ED visit. 
Based on power calculations below, with a 3% repeat OD or death rate for the novel treatment 
group vs. the 11.5% treatment as usual rate in the historical control group, with 99 participants in 
the novel treatment group and 198 participants in the historical control group there will be a 
power of 80% at a type I error rate of 5%. See table below. If there is a less than 3% repeat OD 
rate in the intervention group there will be greater than 80% power.  
 
Fixed Power of 0.80 and sample size for equivalent or non-equivalent numbers of 
participants per group (intervention vs. historical treatment as usual) 
repeated OD/death rate     Stat method                 n1:n2 (1:1, 2:1 or :1 ratio) 
 
11.5%   vs    2%                           Z-test                        86:86          117:59           148:49 
 
                                                     Nonparametric          94:94          148:74           198:66 
 
 
11.5%   vs    3%                            Z-test                       115:115       160:80           204:68 
 
                                                      Nonparametric         131:131       198:99          265:88 

 
 
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14.3 Statistical Hypotheses 
14.3.1 
Primary Endpoint 
The primary hypothesis is that SUBLOCADE is superior to the historical and concurrent control 
group for rates of repeat OD and death during the 6 months treatment period.  
14.4 Analysis Populations 
14.4.1 
Treatment Population  
The Treatment Population includes all subjects who receive at least 1 dose of study medication. 
This population will be used for all safety and efficacy analyses. In the safety analyses, subjects 
will be analysed according to treatment actually received. 
14.5 Planned Analyses 
The analysis will take place once all subjects have completed the trial and sufficient time has 
passed to allow the state death registries to be updated. 
 
14.6 Demographic and Baseline Characteristics Analyses 
Demographic and baseline characteristics, including gender, race, age, weight, height and disease 
history will be summarized by treatment group using descriptive statistics. Disease history will 
include but is not limited to drug use history, history of MAT and previous Ods. Qualitative 
variables, e.g. gender and race will be summarized using frequencies; quantitative variables, e.g. 
age, weight, height will be summarized using e.g. mean, SD, median, minimum and maximum.  
14.7 Efficacy Analysis 
14.7.1 
Primary Efficacy Analysis 
The repeat opioid OD or opioid-related death primary endpoint analysis will be performed using 
Cox proportional regression and compare the SUBLOCADE treatment arm to historical and 
concurrent control data. Propensity scores will be used to match study participants to controls.  
Repeat OD and deaths (measured as time-to-event or censored at 6 months post index OD) will 
be tracked using subject reports, electronic medical records and state death registries. Events will 
be counted within the 6 months of treatment period for all treated subjects. 
Propensity score analysis will be used in the analysis of SUBLOCADE vs. the control for time to 
repeat OD or opioid-related death. Study subjects will receive a propensity score that will be 
matched to propensity scores in the control data.  The propensity score, p, will also be used as a 
weight in the Cox proportional hazards model. All SUBLOCADE treatment group subjects will 
have a weight of p=1 and patients in the control groups will be weighted by p/(1-p).  Here p can 
be viewed as the probability that the control subject would have been a study participant if the 
study were performed during their treatment. 

 
 
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The propensity score will be estimated by fitting a logistic regression on a dataset consisting of 
the consenting subjects (subjects in the SUBLOCADE arm at VCU) and the controls. The 
response variable will be consent to treatment; predictors will include baseline characteristics 
such as subject age, gender, county, race and insurance status. This model will be used to 
generate the predicted probability of consent to participate among the controls. 
The Cox proportional hazards model will use the controls as the reference group and code the 
SUBLOCADE arm as a factor variable. The analysis will test the coefficient for the 
SUBLOCADE arm versus the controls from the Cox regression, with the interpretation of the 
exponential (coefficient) as the hazard ratio for time to repeat OD or opioid-related death in 
subjects consenting to the active treatment group versus the control cohorts. 
The probabilities for the control cohort will be used as weights in the Cox proportional hazards 
model. The weights serve to make the control cohort appear similar to the treatment group on the 
observed baseline characteristics; this will be checked using covariate balance diagnostics. The 
weights will provide greater weight for control patients who likely would have participated if 
offered a prospective trial of SUBLOCADE and lesser weight for patients unlikely to have 
consented. 
In addition, the results will be illustrated with a Kaplan-Meier curve. 
The analysis will take place once all subjects have completed the trial and sufficient time has 
passed to allow the state death registries to be updated. 
14.7.2 
Secondary/Exploratory Endpoint Analysis 
Treatment retention at 3 and 6 months will be analysed utilizing a logistic regression, comparing 
subjects who have primarily intravenous to non-intravenous opioid use as determined using the 
MINI. 
The analysis of the exploratory endpoints (incidence rate of repeat OD, illicit opioid use as 
measured by UDS and opioid craving, as measured by the OC-VAS) is detailed in Table 2. 
These analyses will be performed using the treatment population.  
A summary of the primary, secondary, and exploratory endpoint analyses is shown in Table 2. 

 
 
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Table 2 
Summary of Efficacy Analysis Strategy 
 
Endpoint 
Statistical 
Method 
Analysis 
Population 
Missing Data 
Approach 
Analysis 
Timepoint 
Primary Efficacy Endpoint: 
 
Repeat OD or Death 
Propensity 
scores within 
Cox PH 
Regression 
Treatment 
No imputation  
EOT (6 months) 
Secondary Efficacy Endpoints: 
 
Treatment retention at 3 and 6 
months 
Logistic 
Regression 
Treatment 
No imputation 
EOT (6 months) 
Exploratory Endpoints: 
Illicit opioid use as measured by 
urine drug screen (UDS) results 
Hierarchical 
generalized 
linear 
modeling 
(HGLM)  
Treatment 
Missing UDS 
during treatment 
will be imputed as 
non-negative for 
opioids. Missing 
UDS if lost to 
follow-up will be 
imputed as missing. 
EOT (6 months) 
Opioid craving in subjects as 
measured by Craving Visual Analog 
Scale (VAS) scores. 
Logistic 
Regression, 
ANCOVA  
Treatment 
No imputation 
EOT (6 months) 
Genetic predictors of treatment 
response and repeat OD. 
Logistic 
Regression, 
ANCOVA 
Treatment a 
No imputation 
EOT (6 months) 
Predictability of treatment response 
based on impulse control as 
measured by decision making in the 
delay discounting task. 
Logistic 
Regression, 
ANCOVA 
Treatment 
No imputation 
EOT (6 months) 
Retention in treatment between ED 
initiated Suboxone/Sublocade 
compared to Outpatient initiated 
Suboxone/Sublocade 
Cox PH 
Regression 
Treatment 
No imputation  
EOT (6 months) 
a 
This analysis will only include subjects within the treatment population that consented to participate in the 
PGx sub-study. 
14.7.2.1 
Health Economics & Outcomes Analyses  
Treatment Effectiveness Assessment (TEA) 
 

 
 
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HEOR endpoints relating to the TEA will be described as change from baseline score to each 
follow-up assessment and end of treatment (EOT). Absolute scores by study visit will also be 
reported and compared between treatment groups. The absolute score and/or change from 
baseline score at EOT will be considered the primary variable of interest in these analyses. 
Baseline will be defined as the last assessment on or before Week 3 Day 15±4 (Visit 4). (See 
Appendix 2- Treatment Clinic Schedule of Events) 
 
MEDICATION SATISFACTION QUESTIONNAIRE (MSQ) 
The percentage of subjects reporting each response on the MSQ will be reported by study visit 
and EOT. The percentage of subjects reporting that they are satisfied (score 5-7) at the EOT will 
be considered the primary variable of interest in these analyses.  
 
WORK PRODUCTIVITY ASSESSMENT INSTRUMENT: SPECIFIC HEALTH PROBLEM (WPAI:SHP) 
For the WPAI:SHP, the percentage of patients employed, percentage absenteeism, percentage 
work impairment, and percentage activity impairment will be reported at baseline, each follow-
up assessment and EOT by treatment arm. The change in percent employed from baseline to 
each follow-up assessment will be assessed. Among those employed at baseline and the 
respective follow-up assessments, the changes from baseline in percentage absenteeism, 
percentage work impairment and percentage activity impairment at each follow-up assessment 
will be assessed. The change in percent employed from baseline to EOT; and among those 
employed at baseline and EOT, the changes in percentage absenteeism, percentage work 
impairment and percentage activity impairment from baseline to EOT will be considered as 
primary variables of interest in these analyses.  
Baseline will be defined as the last assessment on or before Week 3 Day 15±4 (Visit 4). (See 
Appendix 2- Treatment Clinic Schedule of Events) 
 
HEALTHCARE RESOURCE UTILIZATION QUESTIONNAIRE(HCRUQ) 
Frequency of use by HCRUQ type will be summed throughout the study period, from Week 1 to 
EOT (or last visit with available data for subjects who discontinue treatment prematurely), to 
arrive at a total use while in the study. The incidence of HCRUQ by type will be assessed, 
dividing by the total amount of follow-up time in each group. Types of hospitalisations, 
emergency room, and outpatient service visits will be categorized (e.g., medical, surgical, 
psychiatric). Hospital days will be calculated as the sum of all inpatient days during the study.  
For continuous measures, 95% confidence intervals will be provided for comparisons of statistics 
between treatments. Unless otherwise specified, the absolute value of continuous outcome 
measures will be analysed using a mixed model for repeated measures (MMRM). A test of 
proportions (for example: exact test) will be used to evaluate treatment differences for 
categorical outcome variables. 

 
 
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14.7.3 
Exploratory Analysis 
Genetic predictors of treatment response and outcomes analysis will include a study of 
polymorphisms in candidate pharmacokinetic and pharmacodynamic genes in subjects that 
consent to the optional PGx sub-study with an aim of understanding the role of genetic variants 
in modifying the risk of future OD and to determine treatment outcomes. This analysis will 
include all subjects that consented to participate in the PGx sub-study. 
The predictability of treatment response based on impulse control analysis will be performed 
using logistic regression models predicting treatment success (e.g., point prevalence opioid 
abstinence, treatment retention) as a function of baseline delay discounting, and opioid 
craving/valuation. Additionally, possible changes in delay discounting and craving/valuation 
over the course of treatment will be modelled using repeated measures analysis of covariance 
(ANCOVA), including time as a within-subjects factor, and relevant demographic and substance 
use measures as covariates. This analysis will be performed using the treatment population.  
14.7.4 
Subgroup Analysis 
Primary analyses will be repeated but adding an explanatory class variable of subjects identified 
as injectors vs. non-injectors at Week 1 Day 1 (Visit 1). 
14.8 Handling of Missing Data 
In general, missing data (caused by premature discontinuation or otherwise) will not be imputed. 
However, missing urine drug screen data will be imputed based on previously defined methods 
in other patient populations. The secondary endpoint is time attending clinic and patients failing 
to appear will be considered to have stopped attending at the date of last visit after they’ve 
missed 5 consecutive visits.  Any missing covariates will be handled via appropriate multiple 
imputation techniques. 
14.9 Analysis of Safety 
Safety variables will include AEs, concomitant medications, laboratory tests (haematology, 
chemistry and urinalysis), vital signs, and medical history. Safety variables will be analysed on 
the treatment population using descriptive statistics for continuous endpoints (e.g. mean, median, 
SD, minimum and maximum) and frequency counts with percentages for discrete endpoints.  
Baseline is defined as the last available assessment prior to dosing on Week 1 Day 1 (Visit 1).  
14.9.1 
Adverse Events 
All AEs will be coded using MedDRA, summarized by treatment arm and reported to FDA. 
Adverse events that begin prior to SUBLOCADE administration or after the 6 month visit will 
be presented separately. Only AEs occurring after SUBLOCADE administration will be included 
in the analysis.  

 
 
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14.9.2 
Extent of Exposure 
The duration of treatment with SUBLOCADE, defined as the date of the last injection minus the 
date of first injection +28 days, will be summarized as a continuous summary.  
The total number of SUBLOCADE injections will be presented as a continuous summary and a 
categorical summary. The number of subjects who had early surgical removal of SUBLOCADE 
depot will be summarized.  
14.9.3 
Laboratory Data  
Summary statistics for absolute laboratory value will be presented.  
14.9.4 
Vital Signs  
Summary statistics for vital signs will be presented.  
14.9.5 
Other Safety-Related Variables  
Medical history will be coded using MedDRA and summarized by treatment group. Body 
weight, height and BMI will be summarized using descriptive statistics (mean, median, SD, 
minimum and maximum), including change from baseline.  
Prior and concomitant medications will be coded using WHO-DD. Incidence (number and 
percent of subjects reporting the medication at least once during the study) will be summarized 
for all concomitant medications.  

 
 
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15 ETHICS AND RESPONSIBILITIES 
15.1 Good Clinical Practice 
The study will be carried out in accordance to the protocol and with local legal and regulatory 
requirements, ICH/GCP and all applicable subject privacy requirements.  
15.2 Institutional Review Board/Independent Ethics Committee 
The protocol, ICF(s) and any other written information and/or materials to be provided to 
subjects will be reviewed by an independent and appropriately constituted IRB/Independent 
Ethics Committee (IEC). If required by local regulations, the protocol should be re-approved by 
the IRB/IEC annually. The IRB/IEC must be constituted and operate in accordance with the 
principles and requirements of ICH/GCP.  
Investigational medicinal product can only be released to the Investigator after documentation 
that all ethical and legal requirements for starting the study has been received by Indivior Inc. or 
designated representative. 
15.3 Informed Consent 
The Investigator or a person designated by the Investigator is to obtain written informed consent 
from each subject prior to entering the study. All written informed consent documents are 
required to have been reviewed and received a favourable opinion/approval from an IRB/IEC 
prior to presenting them to a potential participant.  
The written informed consent process will include the review of oral and written information 
regarding the purpose, methods, anticipated duration and risks involved in study participation. 
The Investigator is to ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided. The Investigator or a person designated by 
the Investigator must also explain to each subject that participation is voluntary, and that consent 
can be withdrawn at any time and without reason. Subjects will receive a signed and dated copy 
of the signed ICF before any study-specific procedures are conducted.  
In the event that new safety information emerges that represents a significant change in the 
risk/benefit assessment, the signed ICF should be updated accordingly. All subjects should be 
informed of the new information, provide their consent to continue in the study, and be provided 
with a signed and dated copy of the revised signed ICF. 
15.4 Records Management 
The Investigator must maintain all study related records (except for those required by local 
regulation to be maintained elsewhere) in a safe and secure location throughout the conduct and 
following the closure of the study. The records must be accessible upon request (e.g., for an 
IRB/IEC, Indivior Inc. or regulatory inspection) along with the facility, study personnel and 
supporting systems/hardware. All documents pertaining to the study, including all versions of the 
approved study protocol, copy of the ICF and other documents as required per local laws and 

 
 
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regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] documents), 
completed CRFs, source records (subject records, subject diaries, hospital records, laboratory 
records, drug accountability records, etc.), and other study-related materials will be retained in 
the permanent archives of the study site. 
Where permitted by local laws and regulations, records may be maintained in a format other than 
hard copy (e.g., electronically in an electronic medical records system). The Investigator must 
ensure that all reproductions are an accurate legible copy of the original and that they meet 
necessary accessibility and retrieval standards. The Investigator must also ensure that a quality 
control process is in place for making reproductions and that the process has an acceptable back-
up of any reproductions. 
The minimum retention time for retaining study records will be in accordance with the strictest 
standard applicable for the study site as determined by local laws, regulations or institutional 
requirements. At a minimum, records will be maintained for 5 years after the end of the study.  

 
 
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16 MONITORING 
In accordance with applicable regulations, GCP, clinical monitor(s) will periodically review all 
study data for accuracy and completeness as described in the Clinical Monitoring Plan.  
The PI must allow the clinical monitor(s) direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the clinical monitor(s) to discuss findings and any 
relevant issues.  
Upon completion of the study, study closeout activities must be conducted in conjunction with 
the PI, as appropriate. 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centres, review of protocol procedures with the investigators 
and associated personnel before the study. Written instructions will be provided for study drug 
preparation and dosing, collection, preparation, and shipment of blood, plasma and urine samples 
are available in the prescribing information.  
This study will be organized, performed, and reported in compliance with the protocol, Standard 
Operating Procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.  
This study is subject to inspections by Regulatory Authorities. If such a regulatory inspection 
occurs, the PI agrees to allow the regulatory inspector direct access to all relevant study 
documents. The PI must contact Indivior Inc. immediately if this occurs and must fully cooperate 
with the inspection conducted at a reasonable time in a reasonable manner.  
 

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

 
 
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18 STUDY REPORTS AND PUBLICATIONS 
A clinical study report will be prepared following completion of the study. Study results will be 
published on clinicaltrials.gov and in a peer reviewed journal. 

 
 
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19 STUDY TERMINATION 
The PI reserves the right to terminate the study at the investigator’s site at any time. Should this 
be necessary, the PI or a specified designee will inform the appropriate Regulatory Authorities of 
the termination of the study and the reasons for its termination, and the PI will inform the 
IRB/IEC of the same. In terminating the study, the PI will assure that adequate consideration is 
given to the protection of the subjects’ interests. 

 
 
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20 CONFIDENTIALITY 
All subject-identifying documentation generated in this study is confidential and may not be 
disclosed to any persons not directly concerned with the study without written permission from 
the subject. However, authorized regulatory officials will be allowed full access to inspect and 
copy the records. All subject bodily fluids and/or other materials collected shall be used solely in 
accordance with this protocol and the ICF signed by the subject, unless otherwise agreed to in 
writing by Indivior Inc. 
Each subject will be identified by initials and an assigned subject number when reporting study 
information to any entity outside of the study centre. Data containing subject identification will 
not be removed from the study centre without first redacting subject identifiers. 

 
 
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21 REFERENCES 
Binswanger, Ingrid A., et al. "Mortality after prison release: opioid overdose and other causes of 
death, risk factors, and time trends from 1999 to 2009." Annals of internal medicine159.9 (2013): 
592-600. 
 
Brazier JE, Roberts J. The estimation of a preference-based measure of health from the SF-12. 
Med Care. 2004 Sep;42(9):851-9. 
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22 APPENDICES 
22.1 Appendix 1 –Schedule of Events – Visit 1 (In ED, inpatient unit or Outpatient Clinic within 7 days 
(168 h) after OD 
 
Procedure / Assessment 
Screening 
Procedures (Visit 
1) 
Treatment Period (Visit 1) 
 
 
Pre-Suboxone 
dose Procedures 
Suboxone Dosing 
Post-Suboxone dose 
Procedures 
Sublocade Dosing 
Post-Sublocade 
dose Procedures 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Brief Physical Examination 
X 
 
 
 
 
 
Concomitant Medications 
Assessment 
X 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
Height/Weight/BMI 
X 
 
 
 
 
 
Breathalyzer 
X 
 
 
 
 
 
Urine Pregnancy Test 
Xb 
 
 
 
 
 
DSM-5 OUD/AUD/SUD 
Checklist 
X 
 
 
 
 
 
Liver function laboratory tests 
(STAT) 
 
Xd 
 
 
 
 
COWS 
 
Xe 
 
X 
 
X 
OC-VAS 
 
Xe 
 
X 
 
 
Delay Discounting Task 
 
X 
 
X 
 
 
Opioid Demand Task 
 
X 
 
X 
 
 
SUBOXONE Test Dose  
 
 
Xf,g 
 
 
 
SUBLOCADE Dose 
 
 
 
 
X 
 
PGx Sampling 
 
 
 
Xa 
 
 
AE Assessment 
 
X 
 
Xg 
 
X 
Clinic appointment visit 
scheduled for next dose 
 
 
 
 
 
X 
AE = adverse event; COWS = Clinical Opiate Withdrawal Scale; MINI = Mini-International Neuropsychiatric Interview  

 
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a. PGx samples will only be taken from subjects that consent to participate in the optional PGx sub-study. 
b. Urine pregnancy test, only for females of child-bearing potential. Results must be available and reviewed prior to Suboxone 
treatment. 
c. Subjects will be included in the study only after it is determined that subject meets all inclusion criteria and none of the 
exclusion criteria.  
d. STAT Local labs will be used for screening liver function tests. Samples must be drawn prior to dosing and will include ALT, 
AST and bilirubin. Abnormal liver function tests (LFTs) will be followed at clinic visits according to investigator’s judgement. 
Liver function tests obtained for clinical reasons will also be used for research purposes if we are unable to obtain blood for 
research purposes. An etiological evaluation will be performed if a hepatic adverse event is suspected. 
e. The COWS and OC-VAS will be completed after consent but prior to first administration of SUBOXONE sublingual film.  
f. Day 1 SUBOXONE/SUBLOCADE Regimen includes supervised administration of 4mg/1 mg SUBOXONE sublingual film, 
followed by 300 mg SUBLOCADE administration.  
g. Subjects will be assessed for adverse events predose and 1-2 hours postdose depending on RASS score prior to discharge.   

 
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22.2 Appendix 2 – Treatment Clinic Schedule of Events – (Week 1 Day 2 – Week 25 Day 169) 
Procedure / Assessment 
Treatment Period 
Visit 2 
Visit 3  
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Wk 1 D 2  
(-0/+3) D 
Wk 2 D 8  
(-0/+4) D 
Wk 3 D 
15 ±4 D 
Wk 4 
D22 (±4) 
D   
Wk 5 
D29 (±4) 
D   
Wk 6 D36 
(-2/+4) D   
Wk 7 D43 
(±4) D   
Wk 8 
D50 (±4) 
D   
Wk 9 D57 
(±4) D   
Wk 10 
D64  
(-2/+4) D   
Counselling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COWS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MINI International 
Neuropsychiatric 
Interview  
X 
 
 
 
 
 
 
 
 
 
Delay Discounting Task 
X 
 
 
 
 
 
 
 
 
 
Opioid Demand Task 
X 
 
 
 
 
 
 
 
 
 
OC-VASa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TEA 
X 
 
X 
 
 
 
 
 
 
 
HCRUQ 
X 
 
X 
 
 
 
X 
 
 
 
MSQ 
X 
 
X 
 
 
 
 
 
 
 
WPAI:SHP 
X 
 
 
 
 
 
 
 
 
 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brief Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Testb 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
SUBLOCADE Injection 
 
X 
 
 
 
X 
 
 
 
X 
Liver function lab tests 
X 
 
 
  
X 
 
 
  
X 
 
Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
HCRUQ = Health Care Resource Utilization Questionnaire; WPAI:SHP = Work Productivity and Activity Impairment Questionnaire: Specific Health Problem  
a. OC-VAS will be assessed prior to SUBLOCADE injection 
b. Urine pregnancy test, only for females of child-bearing potential. Results will be obtained prior to SUBLOCADE injection.  
 
 

 
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Appendix 2 - Treatment Clinic Schedule of Events – (Week 1 Day 2 – Week 25 Day 169) 
 
Procedure / Assessment 
Treatment Period 
 
 
Visit 12 
Visit 13  
Visit 14 
Visit 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 
End of 
Treatment 
/ Early 
Term 
30-Day 
Safety 
Follow-up 
Telephone 
Calld 
 
Wk 11 
D 71 
(±4) D 
Wk 12 
D 78 
(±4) D 
Wk 13 
D 85 
(±4) D 
Wk 14 
D92  
(-2/+4) 
D   
Wk 16 
D106 (±4) 
D   
Wk 18 
D120  
(-2/+4 D   
Wk 20 
D134 
(±4) D   
Wk 22 
D148  
(-2/+4) 
D   
Wk 25 D 
169 (±4) D 
Wk 29 
Day 199 
(±4) D   
Counselling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Drug Screen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Delay Discounting Task 
 
X 
 
 
 
 
 
 
X 
 
Opioid Demand Task 
 
X 
 
 
 
 
 
 
X 
 
OC-VASa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COWS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TEA 
X 
 
 
 
 
X 
 
 
X 
 
HCRUQ 
X 
 
 
X 
 
X 
 
X 
X 
 
MSQ 
X 
 
 
 
 
X 
 
 
X 
 
Employment Question 
X 
 
 
 
 
X 
 
 
X 
X footnote 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy Testb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SUBLOCADE Injection 
 
 
 
X 
 
X 
 
X 
 
 
Liver function laboratory testing 
 
 
X 
 
 
 
X 
 
X 
 
a. OC-VAS will be assessed prior to SUBLOCADE injection 
b. Urine pregnancy test, only for females of child-bearing potential. Results will be obtained prior to SUBLOCADE injection.  
c. All subjects will receive a safety follow-up telephone call 30 days after their EOT/ET visit to assess AEs, SAEs, pregnancy 
status (if applicable) and concomitant medications. Subjects who decline to continue in MAT will receive monthly safety 
follow-up phone calls for an additional 5 months (6 months total) to assess SAEs, pregnancy status (if applicable) and 
concomitant medications.  

 
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22.3 Appendix 3 – Liver Safety 
Monthly monitoring of liver chemistry will occur during the study treatment period.  The 
following should occur if a subject meets any of the liver chemistry stopping criteria as outlined 
in Section 6.4.5 of ￼ of the protocol: 
• Subject should immediately be withdrawn from treatment. Do not re-challenge with study 
treatment. 
• Completed the “Safety Follow-up Procedures” listed below. 
• Upon completion of the safety follow-up, the subject must be withdrawn from the study 
unless further follow-up is required. 
Subjects with ALT > 3x ULN and bilirubin > 2x ULN (> 35% direct); or ALT > 3x ULN 
and INR > 1.5: 
• This event is an SAE and should be reported using the SAE Reporting Form (reference 
Section 11.2. Serum bilirubin fractionation should be performed, if testing is available. If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury). 
Note: INR testing is not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. 
• 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. 
Subjects with ALT > 5x ULN or ALT > 3x ULN who have hepatitis symptoms or rash, 
cannot be monitored for 4 weeks or have elevations that persist ≥ 4 weeks: 
• 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. 
Subjects with ALT > 3x ULN and < 5x ULN and bilirubin < 2x ULN, who do not exhibit 
hepatitis symptoms or rash: 
• Subject may continue study treatment, if liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) can be monitored weekly for up to 4 weeks. 

 
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• If the subject later meets the liver chemistry stopping criteria (outlined in Section 6.4.5 of 
the protocol), 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 < 3x ULN and bilirubin < 2x ULN, subject must be 
monitored twice monthly until liver chemistries normalize or return to within baseline 
values. 
Additional follow-up procedures for subjects who meet any of the liver safety stopping 
criteria: 
• Viral hepatitis serology including: 
• Hepatitis A Immunoglobulin M (IgM) antibody, 
• Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM), 
• Hepatitis C RNA, 
• Cytomegalovirus IgM antibody, 
• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing), and 
• Hepatitis E IgM antibody. 
• Blood sample for PK analysis, obtained within 48 hours of last dose. Record the 
date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw in the eCRF. If the date or time of the last 
dose is unclear, provide the subject’s best approximation. If the date/time of the 
last dose cannot be approximated or a PK sample cannot be collected in the time 
period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are outlined in the laboratory manual. 
• Serum creatine phosphokinase and lactate dehydrogenase. 
• Fractionate bilirubin, if total bilirubin > 2x ULN. 
• Assess eosinophilia. 
• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia) as relevant on the AE eCRF. 

 
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• Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins on the Concomitant 
Medications eCRF. 
• Record alcohol use in the eCRF. 
• In addition, the following are required for subjects with ALT > 3x ULN and 
bilirubin > 2x ULN (< 35% direct) but optional for other abnormal liver 
chemistries: 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies and quantitative total immunoglobulin G 
(IgG or gamma globulins). 
• Serum acetaminophen adduct HPLC assay (quantifies potential 
acetaminophen contribution to livery injury in subjects with definite or 
likely acetaminophen use in the preceding week [James 2009]). 
• Liver imaging (ultrasound, MRI, or CT) to evaluate liver disease. Data 
should be entered into the eCRF, if these tests are performed.