Conditions: Healthy Volunteer Opioid-use Disorder
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 64
Healthy volunteers: yes

Brief summary:
The primary objectives for the study are:

* Part I and Part II: Assess safety and tolerability of repeated doses of INDV-2000 in healthy volunteers.
* Part III: Assess the safety and tolerability of repeated doses of INDV-2000 administered alone and with SUBOXONE sublingual (SL) film in an opioid use disorder (OUD) treatment seeking population.

Detailed description:
The study will be conducted in 3 parts:

Part I: Double-blind, placebo-controlled, randomized, multiple ascending dose study for 7 days of dosing with INDV-2000 in healthy volunteers.

Part II: Double-blind, placebo-controlled, randomized, multiple ascending dose study for 28 days of dosing with INDV-2000 in healthy volunteers.

Part III: This part is an open-label study in OUD treatment seeking individuals.

Arms:
arm 1: Healthy volunteers will receive INDV-2000 100 mg once daily for 7 days. arm 2: Healthy volunteers will receive placebo once daily for 7 days. arm 3: Healthy volunteers will receive INDV-2000 100 mg twice daily for 7 days. arm 4: Healthy volunteers will receive placebo twice daily for 7 days. arm 5: Healthy volunteers will receive INDV-2000 200 mg twice daily for 28 days. arm 6: Healthy volunteers will receive placebo twice daily for 28 days. arm 7: Healthy volunteers will receive INDV-2000 400 mg twice daily for 28 days. arm 8: Healthy volunteers will receive placebo twice daily for 28 days. arm 9: Participants with opioid use disorder will receive SUBOXONE sublingual (SL) film for 6 days during the run-in period. Participants will then receive SUBOXONE SL film alone for 2 days, then SUBOXONE SL film and INDV-2000 for 7 days followed by INDV-2000 dosing alone for 4 days.

Interventions: intervention 1: INDV-2000 intervention 2: Placebo intervention 3: SUBOXONE® sublingual film
Intervention descriptions: intervention 1: Capsule for oral administration intervention 2: Capsule for oral administration intervention 3: Administered either under the tongue (sublingual) or between the gum and cheek (buccal)

Protocol document:
SAP_002.pdf: 
STATISTICAL ANALYSIS PLAN: INDV-2000-102 
Part III
Protocol Title:  A Phase I Double-Blind, Placebo-Controlled 
Randomized Study to Assess Repeated Doses of INDV-2000 
(C4X_3256) up to 28 Days in Healthy Volunteers, and an Open-Label 
Study of INDV-2000 up to 11 Days in Treatment Seeking Individuals 
with Opioid Use Disorder 
Final Version: 04 Dec 2023
NCT: NCT04976855 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
Statistical Analysis Plan 
 
Protocol Title:  
A Phase I Double-Blind, Placebo-Controlled Randomized 
Study to Assess Repeated Doses of INDV-2000 (C4X_3256) 
up to 28 Days in Healthy Volunteers, and an Open-Label Study 
of INDV-2000 up to 11 Days in Treatment Seeking Individuals 
with Opioid Use Disorder 
Protocol Number:    
INDV-2000-102 
Compound Number:  
INDV-2000 (C4X_3256) 
Sponsor Name:  
 
Indivior 
Legal Registered Address:  10710 Midlothian Turnpike, Suite 125 
North Chesterfield, VA 23235 
USA 
IND Number: 
 
145881 
Protocol Version: 
 
Amendment 4.0, Version 5.0 
Date:  
 
 
08 May 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential.  Do not copy, 
circulate, or otherwise distribute without written authorization from  
Indivior Inc. 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
Statistical Analysis Plan Approval  
 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ..........................................................................................1 
TABLE OF CONTENTS ...........................................................................................................3 
LIST OF TABLES .....................................................................................................................5 
LIST OF FIGURES ...................................................................................................................5 
1. INTRODUCTION .................................................................................................................6 
VERSION HISTORY ................................................................................................................6 
1.1. Objectives and Endpoints ...................................................................................................6 
1.2. Study Design .....................................................................................................................10 
2. STATISTICAL HYPOTHESES ..........................................................................................10 
2.1. Multiplicity Adjustment ....................................................................................................11 
3. SAMPLE SIZE DETERMINATION ..................................................................................11 
4. POPULATIONS FOR ANALYSIS .....................................................................................11 
5. STATISTICAL ANALYSES ..............................................................................................11 
5.1. General Considerations .....................................................................................................11 
5.1.1. Timing of Analyses ..................................................................................................11 
5.1.2. Programming Environment ......................................................................................12 
5.1.3. Reporting Conventions ............................................................................................12 
5.1.4. General Analysis Conventions .................................................................................12 
5.1.5. Definitions................................................................................................................12 
5.2. Study Conduct and Participant Disposition ......................................................................13 
5.3. Primary Endpoints Analysis .............................................................................................14 
5.3.1. Definition of Endpoints ............................................................................................14 
5.3.2. Main Analytical Approach .......................................................................................14 
5.4. Exploratory Endpoints Analysis .......................................................................................14 
5.4.1. Definition of Endpoints ............................................................................................14 
5.4.2. Main Analytical Approach .......................................................................................14 
5.5. Other Safety Analyses.......................................................................................................15 
5.5.1. Extent of Exposure ...................................................................................................15 
5.5.2. Adverse Events ........................................................................................................15 
5.5.3. Additional Safety Assessments ................................................................................16 
5.5.3.1. Laboratory Data ..............................................................................................16 
5.5.3.2. Vital Signs .......................................................................................................17 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
5.5.3.3. Electrocardiogram (ECG) Data .......................................................................18 
5.5.3.4. Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................18 
5.6. Other Analyses ..................................................................................................................18 
5.6.1. Demographic and Baseline Characteristics .............................................................18 
5.6.2. Medical History .......................................................................................................19 
5.6.3. Prior and Concomitant Medications and Therapies .................................................19 
5.6.4. Protocol Deviations ..................................................................................................19 
5.7. Interim Analyses ...............................................................................................................19 
6. SUPPORTING DOCUMENTATION .................................................................................19 
6.1. Appendix 1: List of Abbreviations ...................................................................................20 
6.2. Appendix 2: Changes to Protocol-Planned Analyses .......................................................21 
6.3. Appendix 3: Definition and Use of Visit Windows in Reporting .....................................21 
6.4. Appendix 4: Endpoint Derivations ...................................................................................21 
6.4.1. Pharmacokinetic Endpoints .....................................................................................21 
6.4.2. Pharmacodynamic Endpoints...................................................................................21 
6.4.2.1.
 ........................................................................................................21 
6.4.2.2.
 .............................................................................................................22 
6.4.2.3.
 .............................................................................................................22 
6.4.2.4. 
 ..........................................................................................................23 
6.4.2.5. 
...............................................................................................................23 
6.4.3. Safety Endpoints ......................................................................................................23 
6.4.3.1.
..................................................................................................23 
6.5. Appendix 5: Statistical Methodology Details ...................................................................23 
6.5.1. PK Analysis .............................................................................................................23 
6.5.1.1. Concentration ..................................................................................................23 
6.5.1.2. PK Parameters .................................................................................................24 
6.6. Appendix 6: Methods to Manage Missing Data ...............................................................24 
6.6.1. Rule for Missing Pre-dose Concentrations ..............................................................24 
6.6.2. Missing Pre-dose Sampling Date/Times ..................................................................25 
6.6.3. BLQ Concentrations ................................................................................................25 
6.6.4. Exposure ..................................................................................................................25 
6.6.5. AEs ...........................................................................................................................25 
6.6.6. Medications and Therapies ......................................................................................26 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
6.7. Appendix 7: Data Set Descriptions ...................................................................................27 
7. REFERENCES ....................................................................................................................27 
 
LIST OF TABLES 
Table 1 
SAP Version History Summary ..................................................................6 
Table 2   
Study Objectives and Estimands ................................................................7 
Table 3 
Analysis Populations ................................................................................11 
Table 5 
Planned Laboratory Evaluations ...............................................................17 
 
LIST OF FIGURES 
Figure 1. 
Study Schematic .......................................................................................10 
 
 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
1. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study INDV-2000-102 Part III and is based on 
Protocol Amendment 4/09 May 2023 (Version 5.0). This SAP supersedes the statistical 
considerations stated in the protocol; any differences are identified in Appendix 2 of this 
document. However, major modifications of the primary endpoint definition or its analysis 
will also be reflected in a protocol amendment. Post hoc or unplanned analyses not specified 
in the SAP will be documented in the clinical study report (CSR). 
VERSION HISTORY 
Table 1 
SAP Version History Summary 
 
1.1. Objectives and Endpoints 
Each study objective is presented in Table 2 with associated estimands. Intercurrent events 
occur after treatment starts and either preclude the observation of an endpoint or affect its 
interpretation. For the intercurrent event of study discontinuation, the principal stratum 
strategy will be used for pharmacokinetic (PK) endpoints in that only subjects with an 
adequate amount of PK data will be included in the PK population; for all other endpoints, 
the while-on-treatment strategy will be used since data will be collected only up to end of 
study (EOS) or study discontinuation. Other potential intercurrent events in this study are 
prohibited medications and lifestyle restrictions detailed in protocol sections 9.6.2 and 9.6.3, 
respectively. Possible strategies for these intercurrent events are treatment policy 
(intercurrent event is ignored), while on treatment (data collected after the event is ignored), 
and principal stratum for PK endpoints (subject is excluded from the PK population), to be 
decided by the sponsor on a case-by-case basis. 
 
SAP 
Version 
SAP 
Finalization 
Date 
Associated 
Protocol 
Amendment 
Protocol 
Approval  
Date 
Change 
Rationale 
1.0 
 
04Dec2023 
Amendment 
4.0,  
Version 5.0 
 
09May2023 
Not Applicable 
 
Original version 
 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
Table 2   
Study Objectives and Estimands 
  
Estimand 
Objective 
Clinical Category 
Statistical 
Category 
 
Variable/Endpoint 
Pop-
ulation 
 
Population-Level Summary 
Primary Objective 
Assess the safety and tolerability following repeated doses of INDV-2000 administered alone and with SUBOXONE sublingual (SL) film in an 
opioid use disorder (OUD) treatment seeking population. 
Adverse Events (AEs) 
Primary 
Incidence, severity, and relatedness of treatment-emergent 
adverse events (TEAEs), serious adverse events (SAEs) and 
events leading to study discontinuation or death. 
Safety 
Categorical descriptive 
Exploratory Objectives 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
  
Estimand 
Objective 
Clinical Category 
 
Statistical 
Category 
 
 
Variable/Endpoint 
 
Pop- 
ulation 
Population-Level Summary 


 
 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
  
Estimand 
Objective 
Clinical Category 
Statistical 
Category 
 
Variable/Endpoint 
Pop-
ulation 
Population-Level Summary 
 
 
 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
1.2. Study Design 
This is a Phase I study to assess repeated doses of INDV-2000 in healthy volunteers and in 
treatment-seeking individuals with OUD. The study will be conducted in three parts, as 
depicted in Figure 1. This SAP is for Part III only. 
Figure 1. Study Schematic 
  
 
 
 
 
 
 
 
 
 
 
 
Key features of the study design are described below. 
• Part III is an open-label study in OUD treatment-seeking individuals.  
• Part III dose determination will follow a blinded review of safety and PK data from Parts 
I and II.  
• The screening period for Part III is up to 35 days. Subjects will receive SUBOXONE SL 
film during a 6-day, in-clinic run-in period. Qualifying subjects will then be enrolled into 
the study, consisting of a 14-day in-clinic period followed by an EOS visit on Day 21. 
Subjects will receive SUBOXONE SL film alone on Days 1 and 2, SUBOXONE SL film 
and INDV-2000 on Days 3-9, and INDV-2000 alone on Days 10-13. Total study duration 
per subject, from screening through the EOS visit, will be approximately 56 days. 
2. STATISTICAL HYPOTHESES 
There will be no statistical inference in this study. All statistics will be descriptive only. 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
2.1. Multiplicity Adjustment 
There will be no statistical inference in this study; therefore, there will be no need for 
multiplicity adjustment. 
3. SAMPLE SIZE DETERMINATION 
The sample size for each part of the study is not based on formal power calculations because 
the study is designed to provide preliminary descriptive assessments of the safety, tolerability 
and PK for INDV-2000. The sample sizes used are typical for studies of this nature and 
should be adequate to assess the parameters described. 
4. POPULATIONS FOR ANALYSIS 
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population shown in Table 3 prior to releasing the database and classifications 
will be documented per standard operating procedures. 
Table 3 
Analysis Populations 
 
5. STATISTICAL ANALYSES 
5.1. General Considerations 
5.1.1. Timing of Analyses 
Database lock and final production of tables, figures, and listings (TFLs) will occur after the 
completion of Part III. 
Population 
Description 
Screened 
Subjects who signed informed consent. 
Enrolled 
Subjects who met Day -1 run-in assessment criteria. 
Safety  
Subjects who received at least one dose of investigational 
medicinal product (IMP). Subjects will be summarized 
according to the study treatment received.  
Run-In Safety 
Subjects who received at least one dose of study drug during 
the run-in period. 
PK 
Subjects who received at least one dose of INDV-2000, have an 
adequate number of PK samples collected to derive any PK 
parameter, and have no protocol deviations that would 
significantly alter plasma concentration of INDV-2000. 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
5.1.2. Programming Environment 
SAS® version 9.4 or higher (SAS Institute, Cary, North Carolina) will be used for statistical 
analyses and for the production of Study Data Tabulation Model (SDTM) and Analysis Data 
Model (ADaM) data sets as well as TFLs.  
5.1.3. Reporting Conventions 
Data will be summarized by visit for visit-based assessments and by treatment for non-visit-
based assessments, if applicable. TFL tables of contents, mock-ups, and specifications are 
provided in a separate document from the SAP. The following reporting conventions will be 
followed: 
• Treatment group names and order in tables and figures for non-visit-based assessments, 
where applicable, will be SUBOXONE, INDV-2000+SUBOXONE, INDV-2000, All 
Subjects; some of these tables may omit the All Subjects groups. Tables and figures for 
visit-based assessments will only show All Subjects and will include a footnote to 
describe treatments administered for each visit, if applicable. 
• Tables and figures will present summaries/analyses by study visit and time point, if 
applicable, for visit-based assessments.  
• Table column headers and figure legends will include subgroup sample sizes (“N = xx”). 
Sample sizes reported as part of descriptive statistics (“n”) will be the number of non-
missing observations. 
• Listings will generally include unique subject identifier (including site identifier); 
treatment, if applicable, if the assessment is not visit-based; study visit/time point; 
assessment or collection date/time; parameter; and observed value.  
5.1.4. General Analysis Conventions 
Categorical variables will be summarized using frequencies and percentages.  Percentages 
will be reported to one decimal place.  
Continuous variables will be summarized using descriptive statistics (e.g., n, mean, standard 
deviation (SD), distribution percentiles, range). The number of decimal places for minimums 
and maximums will be the same as the source data. The number of decimal places for means, 
medians, and interquartile ranges will be the same as the source data plus one, and the 
number of decimal places for measures of variance will be the same as the source data plus 
two. See Section 6.5 (Appendix 5) for summary statistics and precision specifications for PK 
data. 
Data with qualifiers (e.g., “<”) will be listed with but summarized without the qualifier. 
5.1.5. Definitions 
IMP: INDV-2000 or placebo (placebo not applicable in Part III) 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
Study Drug: INDV-2000, SUBOXONE SL film, or placebo (placebo not applicable in Part 
III). 
Screening Period: Informed consent to Day -7 Clinic Check-In. 
Run-In Period: Day -7 to Day -1 Run-In Assessment 
End-of-Study (EOS): Early termination or completion of last scheduled visit. 
Enrolled Subject: Met Day -1 run-in assessment criteria. 
Study Day 1: day of first dose of study drug administration after the run-in period. 
Study day:  
• Study day = date of assessment – date of Study Day 1 + 1, for assessments on or after 
Study Day 1 
• Study day = date of assessment – date of Study Day 1, for assessments before Study Day 
1 
Study time: time of assessment – time of first study drug administered in the clinical unit. 
Duration:  
• Duration in days = end date – start date + 1 
• Duration in minutes = end time – start time. Durations will be adjusted for Daylight 
Saving Time, where applicable. 
Baseline observation: for a given parameter for a given subject, the last observed value, 
including unscheduled and repeated assessments, before the first dose of IMP or planned first 
dose of IMP if IMP was not administered. 
Run-in baseline observation: for a given parameter for a given subject, the last observed 
value, including unscheduled and repeated assessments, before the first dose of study drug 
during the run-in period. 
5.2. Study Conduct and Participant Disposition 
Subject disposition summaries will include the number of subjects who were screened for 
Part III, who were screen failures, who were run-in failures, who were enrolled, who were in 
each analysis population, and who completed the study. For percentages, the number of 
subjects screened will be the denominator for screen and run-in failures and for the Run-In 
Safety Population, which in turn will be the denominator for subjects enrolled. The number 
of subjects enrolled will be the denominator for the Safety and PK analysis populations and 
for subjects completing the study. 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
Reason for study discontinuation will be summarized by number and percentage of subjects 
for each reason reported; for the percentage, the number of subjects who discontinued will be 
the denominator. 
Reason for screen failure will be summarized in a separate table by number and percentage 
of subjects for each reason reported; the denominator will be the number of screen failures. 
5.3. Primary Endpoints Analysis 
5.3.1. Definition of Endpoints 
The primary endpoints are incidence of TEAEs, maximum severity TEAEs, TEAEs related 
to study drug, treatment-emergent serious adverse events (TESAEs), and TEAEs leading to 
study discontinuation or death.  
5.3.2. Main Analytical Approach 
Estimand strategy: While on treatment. 
Analysis set: Safety (see Table 3).   
Analysis methodology:  Descriptive only.  
Intercurrent events and missing data:  AE data will no longer be collected on subjects who 
discontinue early from the study except as required to resolve an ongoing AE. See Section 
6.6.3 (Appendix 6) for details on handling of missing AE information.  
See Section 5.6.2 for details on AE summaries and listings. 
5.4. Exploratory Endpoints Analysis 
5.4.1. Definition of Endpoints 
5.4.2. Main Analytical Approach 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
5.5. Other Safety Analyses 
5.5.1. Extent of Exposure 
Study drug exposure will be summarized as total number of doses and dose duration (days), 
separately for INDV-2000 (Safety Population) and buprenorphine (Run-In Safety 
Population). For INDV-2000, exposure will be summarized for study days 3-9 (with 
buprenorphine), study days 10-13 (without buprenorphine) and study days 3-13. For 
buprenorphine, exposure will be summarized for run-in, study days 1-2 (without INDV-
2000), study days 3-9 (with INDV-2000), and study days 1-9. 
5.5.2. Adverse Events 
A TEAE is an AE that started at or after first administration of IMP. A run-in AE is an AE 
that started at or after first administration of study drug during the run-in period. AEs will be 
assigned to study treatments based on start dates and times of treatments and start dates and 
times of AEs. 
AEs will be coded to a System Organ Class (SOC) and Preferred Term (PT) using Medical 
Dictionary for Regulatory Activities (MedDRA). Additional details of the coding process, 
including the current version of the dictionary, are described in the Data Management Plan.  
All AEs will be listed for individual subjects. Listings will include SOC, PT, and reported 
term; treatment; onset date and time, end date, and duration; run-in status, treatment-
emergence, severity, toxicity grade (though not required for Part III of the study), seriousness 
and seriousness criteria; relationship to study drug; action taken with IMP; action taken with 
SUBOXONE SL film; whether concomitant treatment was given; outcome; and whether the 
AE resulted in study discontinuation. Duration (days) is calculated as the AE end date – the 
AE onset date +1; for ongoing AEs, the date of end of study participation will be used as the 
end date. Duration will be missing if either the start or end date is partially or completely 
missing. SAEs, TEAEs leading to IMP discontinuation or interruption, AEs leading to 
SUBOXONE SL film discontinuation or interruption, and fatal AEs will be listed separately. 
The incidence and number of all TEAEs, TESAEs, study drug-related TEAEs and TESAEs, 
severe TEAEs, TEAEs leading to IMP discontinuation or interruption, and fatal TEAEs will 
be presented in an overall summary table.  
TEAEs, TESAEs, study drug-related TEAEs and TESAEs, and run-in AEs will be 
summarized by MedDRA SOC and PT, each in descending order of frequency among all 
subjects within study part (then alphabetically in case of ties). TEAEs will also be 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
summarized by maximum severity within SOC and PT. If an AE is reported more than once 
by a subject within a SOC and/or PT, the maximum reported level of severity will be used at 
each level of summation in the severity summary table.  
Incidence and number of TEAEs will also be summarized by PT only (ie, not SOC), sorted 
by descending frequency among all subjects (within study part). 
Non-treatment-emergent, non-run-in AEs are defined as AEs that started either before first 
administration of study drug or after the run-in period but before first administration of IMP 
and will be summarized for the run-in safety population. 
See Section 6.6.3 (Appendix 6) for details on handling of missing AE information. 
5.5.3. Additional Safety Assessments 
5.5.3.1. Laboratory Data 
Planned laboratory evaluations (Table 5) will be summarized by analysis visit as observed 
values and, for numeric values, changes from baseline. Normal/abnormal shifts from baseline 
will also be summarized. Abnormal laboratory evaluations will be listed separately. 
Laboratory evaluations done only at screening and during run-in will be listed but not 
summarized, unless included as baseline observation. Reported values of clinical laboratory 
parameters that include qualifiers (ie, <, ≤, >, ≥) will be listed as reported but will be 
summarized without the qualifier. 
 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
Table 4 
Planned Laboratory Evaluations 
Haematology 
Haematocrit 
Haemoglobin 
Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with differential (absolute count) 
 
Urinalysis: 
Appearance 
Bilirubin 
Colour 
Glucose 
Ketones 
Leucocyte esterase 
Microscopic examination of sedimenta 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Pregnancy: 
Serum hCG 
Urine hCG 
 
Molecular 
PCR for COVID-19 
 
Screening Only: 
FSH (as needed in post-menopausal females only) 
Haemoglobin A1c 
Hepatitis B surface Antigen 
Hepatitis C Antibody 
HIV-1 and -2 antibodies 
Prothombin Time with INR 
PTT  
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase 
Gamma-glutamyl transferase 
Glucose (non-fasting) 
Lactate dehydrogenase 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
 
Urine Drug Screen (UDS): 
Opioids 
Cocaine 
Amphetamines 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 
Ethanol 
In addition to the above, for Part III: 
Fentanyl 
Oxycodone 
 
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; 
INR = international normalized ratio; and PTT = partial thromboplastin time. 
a 
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation 
are positive (microscopic examination may include but is not limited to White Blood Cell count, Red Blood 
Cell count, casts and crystals).  
5.5.3.2. Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, temperature) 
will be summarized as observed values and changes from baseline by analysis visit and time 
point. Vital signs during the run-in period will be summarized separately.  


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
5.5.3.3. Electrocardiogram (ECG) Data 
Numeric 12-lead ECG parameters [heart rate, PR interval, QRS duration, QT interval, 
Fridericia’s corrected QT interval (QTcF)] will be summarized as observed values and 
changes from baseline by analysis visit and time point. ECG interpretation (normal, abnormal 
not clinically significant, abnormal clinically significant) will be summarized by visit and 
time point as shifts from baseline. 
5.5.3.4. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The composite endpoints Suicidal Ideation and Suicidal Behavior will be derived from the 
following 10 binary C-SSRS questions, reordered from the actual scale to facilitate the 
derivation: 
 
Question 1  
Wish to be Dead 
Question 2  
Non-specific Active Suicidal Thoughts 
Question 3  
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Question 4 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Question 5 
Active Suicidal Ideation with Specific Plan and Intent 
Question 6 
Preparatory Acts or Behavior 
Question 7  
Aborted Attempt 
Question 8 
Interrupted Attempt 
Question 9 
Actual Attempt (non-fatal) 
Question 10 
Completed Suicide 
Suicidal Ideation is derived as “yes” if any of Question 1-5 has a “yes” response. Suicidal 
Behavior is derived as “yes” if any of Question 6-10 has a “yes” response. If there are zero 
“yes” responses and at least one question has a missing response, the derived composite will 
be missing. Suicidal Ideation and Suicidal Behavior will be summarized as categorical 
variables by analysis visit. 
5.6. Other Analyses 
5.6.1. Demographic and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized separately for the run-in 
safety, safety, and PK populations, if different. Parameters to be summarized will be age, sex, 
race, ethnicity, fertility status, height/weight/body mass index, and substance use (alcohol, 
nicotine, xanthine/caffeine) status (never/current/former). Listings will include all subjects, 
including screen failures and run-in failures. 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
5.6.2. Medical History 
Relevant medical history will be coded using MedDRA (refer to the Data Management Plan) 
and will be listed for the run-in safety population. 
5.6.3. Prior and Concomitant Medications and Therapies 
Medications and therapies will be collected from screening through EOS and will be coded 
using Anatomical Therapeutic Chemical (ATC) classification codes via the World Health 
Organization Drug Dictionary (WHO-DD). Additional details of the coding process, 
including the current version of the dictionary, are described in the Data Management Plan. 
Prior medications and therapies will be medications/therapies that ended before first 
administration of study drug or were taken by subjects who did not take study drug. 
Therapies and medications that were started or were ongoing during run-in will be 
considered run-in therapies and medications. Therapies and medications that were started or 
were ongoing post run-in will be considered concomitant therapies and medications. A 
therapy or medication can be both run-in and concomitant. Therapies/medications will be 
assigned to study treatments based on start dates and times of treatments and start and end 
dates and times of therapies/medications. 
Prior concomitant medications and therapies will be summarized for all subjects. Run-in 
medications and therapies will be summarized for the run-in safety population. Concomitant 
medications and therapies will be summarized for the safety population. The summary of 
incidence (number and percentage of subjects reporting the medication/therapy at least once) 
will be sorted alphabetically by therapeutic class (ATC level 2) and standardized 
medication/therapy name.  
See Section 6.6.4 (Appendix 6) for details on handling missing information on medications 
and therapies. 
5.6.4. Protocol Deviations 
Protocol deviations will be identified and documented prior to database lock and will be 
summarized by category (eg, prohibited medication, out-of-window assessment) and type 
(eg, major, minor), per the Protocol Deviation Plan for the study, for the run-in safety 
population. Deviations that occur in subjects who were not dosed with study drug, if any, will 
be summarized separately. All protocol deviations will be listed.  
5.7. Interim Analyses  
Not applicable. 
6. SUPPORTING DOCUMENTATION 
 




 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
6.2. Appendix 2: Changes to Protocol-Planned Analyses 
The following are changes from the protocol that are in the SAP: 
Protocol: 
SAP: 
 
Added Screened analysis population. 
 
Added Enrolled analysis population. 
6.3. Appendix 3: Definition and Use of Visit Windows in Reporting 
No windowing will be used for summaries. Analysis visits will be visits denoted in the Case 
Report Form (CRF). If a subject has more than 1 assessment for a given visit, the most recent 
non-missing assessment will be used for summaries.   
6.4. Appendix 4: Endpoint Derivations 
6.4.1. Pharmacokinetic Endpoints 
6.4.2. Pharmacodynamic Endpoints 
 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
6.4.3. Safety Endpoints 
6.5. Appendix 5: Statistical Methodology Details 
Statistical programming will be done using SAS version 9.4 (or later) on a Windows 10 
Enterprise (or later) operating system. Plasma PK parameters will be calculated using 
Phoenix™ WinNonlin® (Version 8.3.4, Certara, LP).  
6.5.1. PK Analysis 
6.5.1.1. Concentration 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
6.5.1.2. PK Parameters 
 
6.6. Appendix 6: Methods to Manage Missing Data 
6.6.1. Rule for Missing Pre-dose Concentrations 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
6.6.2. Missing Pre-dose Sampling Date/Times 
If a missing pre-dose concentration is also missing sampling date/time (due to the sample not 
being drawn), the sampling date/time will be imputed with the corresponding dosing date/time 
on that day. 
6.6.3. BLQ Concentrations 
Concentration values that are reported as BLQ will be presented as “BLQ” in concentration 
listings, replaced by 0 for summary statistic calculations and linear-scale plots of 
concentrations, and excluded from semi-logarithmic-scale plots of concentrations.  
 
For derivations of PK plasma parameters, all concentrations that are BLQ prior to the first 
measurable concentration will be set to zero. BLQ values that are between measurable 
concentrations will be set to missing. Measurable concentrations immediately between 2 BLQ 
values will be set to missing. Measurable concentrations following two or more consecutive 
BLQ concentrations will be set to missing. The BLQ values following the last quantifiable 
time points will be set to missing. No concentration estimates will be imputed for missing 
sample values. 
6.6.4. Exposure 
Missing Study Drug Dosing Information 
All efforts should be made to obtain missing study drug dosing information from the 
investigator.  If data are still missing after all efforts, then total exposure will be missing.  
 
Missing Last Date of Study Drug Exposure 
All efforts should be made to obtain missing last date of study drug exposure from the 
investigator.  If the last date of exposure is still missing after all efforts, then the last available 
dosing record date may be used as the last study drug exposure date for the calculation of 
exposure duration.  
 
6.6.5. AEs 
Missing AE Severity 
Missing AE severity must be queried until resolution. In the unlikely event that resolution is 
not possible, missing severity will be imputed as “severe” in summaries. 
 
Missing AE Relationship to Study Drug  
Missing relationship to study drug for a TEAE must be queried until resolution. In the 
unlikely event that resolution is not possible, missing relationship will be imputed as “related” 
in summaries.  
 
Missing AE Seriousness 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
Missing AE seriousness must be queried until resolution. Seriousness cannot be imputed as 
“serious” since doing so would affect the reconciliation between the trial database and the 
SAE registry.  
 
Missing AE Start Date/Time Information 
Note: partial times will not be recorded in the CRF. 
An AE will be considered a run-in AE for the Run-In Safety Population under the following 
conditions: 
• Missing start year, month, day, time and it can be deduced from non-missing components 
of AE end date that the AE ended before first IMP. 
 
• Missing start month, day, time if start year is equal to or after year of first study drug 
during run-in and it can be deduced from non-missing components of AE end date that AE 
ended before first IMP. 
 
• Missing start day and time if start year is after year of first study drug during run-in or if 
start year is equal to year of first study drug during run-in and month is equal to or after 
month of first study drug during run-in and it can be deduced from non-missing 
components of AE end date that AE ended before first IMP. 
 
• Missing start time if start date is on or after date of first study drug during run-in and it 
can be deduced from non-missing components of AE end date that AE ended before first 
IMP. 
An AE will be considered treatment emergent for the Safety Population under the following 
conditions: 
• Missing start year, month, day, time unless it can be deduced from non-missing 
components of AE end date that the AE ended before first IMP. 
 
• Missing start month, day, time if start year is equal to or after year of first IMP, unless it 
can be deduced from non-missing components of AE end date that AE ended before first 
IMP. 
 
• Missing start day and time if start year is after year of first IMP or if start year is equal to 
year of first IMP and month is equal to or after month of first IMP, unless it can be 
deduced from non-missing components of AE end date that AE ended before first IMP. 
 
• Missing start time if start date is on or after date of first IMP. 
6.6.6. Medications and Therapies 
Missing End Date/Time Information 
Note: partial times will not be recorded in the CRF. 
Run-in and concomitant status will be assigned as follows: 
A medication/therapy will be considered run-in under the following conditions: 


 
 
SAP for Protocol INDV-2000-102 Part III 
INDV-2000 (C4X_3256) 
• Missing end year, month, day, time and it can be deduced from non-missing components 
of the start date that the medication/therapy started before or during run-in. 
 
• Missing end month, day, time if end year is equal to or after start year of run-in and it can 
be deduced from non-missing components of the start date that the medication/therapy 
started before or during run-in. 
 
• Missing end day and time if end year/month is equal to or after start year/month of run-in 
and it can be deduced from non-missing components of the start date that the 
medication/therapy started before or during run-in. 
 
• Missing end time if end date is on or after start date of run-in and it can be deduced from 
non-missing components of the start time that the medicaton/therapy started before or 
during run-in. 
A medication/therapy will be considered concomitant under the following conditions: 
• Missing end year, month, day, time and it can be deduced from non-missing components 
of the start date that the medication/therapy started before or during post run-in. 
 
• Missing end month, day, time if end year is equal to or after start year of post run-in and it 
can be deduced from non-missing components of the start date that the medication/therapy 
started before or during post run-in. 
 
• Missing end day and time if end year/month is equal to or after start year/month of post 
run-in and it can be deduced from non-missing components of the start date that the 
medication/therapy started before or during post run-in. 
 
• Missing end time if end date is on or after start date of post run-in and it can be deduced 
from non-missing components of the start time that the medicaton/therapy started before 
or during post run-in. 
6.7. Appendix 7: Data Set Descriptions 
Trial data sets will consist of CRF exports and external data files. External files may be used 
for protocol deviations and data from the central laboratory, for example. 
7. REFERENCES 
None. 

Prot_000.pdf: 
CLINICAL STUDY PROTOCOL: INDV-2000-102 
Protocol Title: A Phase I Double-Blind, Placebo-Controlled 
Randomized Study to Assess Repeated Doses of INDV-2000 
(C4X_3256) up to 28 Days in Healthy Volunteers, and an 
Open-Label Study of INDV-2000 up to 11 Days in Treatment 
Seeking Individuals with Opioid Use Disorder 
Protocol Number: INDV-2000-102 
Original Protocol Date: 15 Apr 2021
Amendment Number/Date: Amendment 4/ 09 May 2023 
NCT: NCT04976855 


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CLINICAL STUDY PROTOCOL: INDV-2000-102 
Protocol Title: 
A Phase I Double-Blind, Placebo-Controlled Randomized Study to 
Assess Repeated Doses of INDV-2000 (C4X_3256) up to 28 Days in 
Healthy Volunteers, and an Open-Label Study of INDV-2000 up to 
11 Days in Treatment Seeking Individuals with Opioid Use Disorder 
Protocol Number: 
INDV-2000-102 
Product Name: 
INDV-2000 
Development 
Phase: 
1 
IND Number: 
145881 
Indivior Legal 
Registered 
Address: 
Indivior 
10710 Midlothian Turnpike, Suite 125 
North Chesterfield, VA 23235 
USA
Original Protocol 
Date: 
15 April 2021 
Amendment 
Number/Date: 
Amendment 4/ 09 May 2023 (Version 5.0) 
Confidentiality Statement 
This document is a confidential communication of Indivior. The recipient agrees that no 
unpublished information contained herein will be published or disclosed without prior 
written approval of Indivior, except that this document may be disclosed to appropriate 
ethics committees or duly authorized representatives of the US Food and Drug 
Administration or other responsible Regulatory Authorities under the condition that they are 
requested to keep it confidential.  


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CLINICAL PROTOCOL SIGNATURE PAGE 
Protocol Title: 
A Phase I Double-Blind, Placebo-Controlled Randomized Study to 
Assess Repeated Doses of INDV-2000 (C4X_3256) up to 28 Days in 
Healthy Volunteers, and an Open-Label Study of INDV-2000 up to 
11 Days in Treatment Seeking Individuals with Opioid Use Disorder 
 
Protocol Number: 
INDV-2000-102 
 
Protocol Version 
Number: 
v 5.0 
Protocol Version 
Date: 
09 May 2023 
 
 
This clinical study protocol was subject to critical review and has been approved by the 
appropriate protocol review committee of Indivior. The information contained in this protocol is 
consistent with: 
 The current risk-benefit evaluation of the investigational medicinal product. 
 The moral, ethical and scientific principles governing clinical research as set out in the 
principles of International Council on Harmonisation (ICH) E6 (Good Clinical Practice) and 
according to applicable local laws and regulations. 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational medicinal product. 


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STUDY PERSONNEL INFORMATION 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES   
  
Document History 
Document:   
Date:  
Amendment 4
09 May 2023
Amendment 3
28 July 2022
Amendment 2
15 July 2022
Amendment 1
18 May 2022
Original Protocol
15 Apr 2021
 
Amendment 4 (09 May 2023) 
 
Section Number(s) and 
Name(s) 
Description of Change 
Brief Rationale 


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INDV-2000 
 
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A Phase I Double-Blind, Placebo-Controlled Randomized Study to 
Assess Repeated Doses of INDV-2000 (C4X_3256) up to 28 Days in 
Healthy Volunteers, and an Open-Label Study of INDV-2000 up to 11 
Days in Treatment Seeking Individuals with Opioid Use Disorder. 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to this 
investigational medicinal product (IMP) is the confidential and proprietary information of 
Indivior, and except as may be required by local laws or regulation, may not be disclosed to 
others without prior written permission of Indivior. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. My staff and/or I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
International Council on Harmonisation E6 / Good Clinical Practice guidelines and will make a 
reasonable effort to complete the study within the time designated. 
I agree to ensure all associates, colleagues and employees delegated to assist with the conduct of 
the study are trained on this study protocol and amendments, other study-related materials and 
are qualified to perform their delegated tasks. I will provide all study personnel copies of the 
protocol and any amendments and grant access to all information provided by Indivior or 
specified designees. I will discuss the material with them to ensure that they are fully informed 
about the IMP and appropriate information throughout the study. Mechanisms are in place to 
ensure that site staff receives the appropriate information throughout the study. 
 


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SYNOPSIS 
Protocol Title: 
A Phase I Double-Blind, Placebo-Controlled Randomized Study to Assess Repeated Doses of 
INDV-2000 (C4X_3256) up to 28 Days in Healthy Volunteers, and an Open-Label Study of 
INDV-2000 up to 11 Days in Treatment Seeking Individuals with Opioid Use Disorder 
Protocol Number: 
INDV-2000-102 
Study Rationale: 
Target Population: 
Part I and Part II: Healthy male and female volunteers aged 18 to 55 years, body mass index 
(BMI) 18.0 to 32.0 kg/m². 
Part III: Treatment seeking male and female subjects with a DSM-5 diagnosis of moderate or 
severe OUD aged 18 to 65 years, BMI 18.0 to 35.0 kg/m².


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Number of Subjects: 
Part I (2 cohorts) and Part II (2 cohorts): Each cohort will be composed of 12 healthy 
volunteers (9 receiving active and 3 placebo). A total of 48 healthy male and female volunteers 
total are planned to participate in both parts. 
Part III: A single group of up to 16 treatment seeking subjects with OUD.  
Duration of Study: 
Part I: The study will be an INDV-2000 multiple ascending dose study. Total study duration 
per cohort inclusive of Screening through the End of Study (EOS) visit is approximately 42 
days. 
Part II: The study will be an INDV-2000 multiple ascending dose study. Total study duration 
per cohort inclusive of Screening through the EOS visit is approximately 63 days. 
Part III: This study will be open-label dosing of INDV-2000. Total study duration inclusive of 
Screening through the EOS visit is approximately 56 days.  
For study Parts I and II, male participants will complete a safety phone call 90 days after their 
last dosing day to assess any new pain, swelling or nodular lesions in scrotum.
Objectives: 
The primary objectives for the study are: 
Part I and Part II  
 Assess safety and tolerability of INDV-2000 following repeated doses of INDV-2000 in 
healthy volunteers. 
Part III 
 Assess the safety and tolerability following repeated doses of INDV-2000 administered 
alone and with SUBOXONE sublingual (SL) film in an OUD treatment seeking 
population. 
The secondary objectives for the study are: 
Part I and Part II 
 Characterize the pharmacokinetic (PK) profile following multiple doses of INDV-2000. 
The exploratory objectives for the study are: 


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Study Design: 
The study will be conducted in 3 parts: 
Part I: Double-blind, placebo-controlled, randomized, multiple ascending dose study for 7 
days of dosing with INDV-2000 in healthy volunteers. The screening period is up to 28 days. 
In each cohort, healthy volunteers will reside at the clinical unit from the evening of Day -1 to 
the morning of Day 8. In Cohort 1, doses will be administered once daily in the morning of 
Days 1-7. In Cohort 2, doses will be administered twice daily during Days 1-7. Healthy 
volunteers will be discharged on Day 8 except in the case the Investigator judges it appropriate 
to retain the healthy volunteer to address safety concerns until resolution. The EOS visit will 
be performed on Day 14 which is one week after the last dose. Male participants will complete 
a safety phone call 90 days after their last dosing day to assess any new pain, swelling or 
nodular lesions in the scrotum. Two cohorts are planned, where each cohort will utilize a 
different dose, and all healthy volunteers within the same cohort will receive the same dose. 
The dose escalation decision for Part I, Cohort 2 will be based on a blinded review of TEAEs, 
concomitant medications, vital signs, ECGs, clinical laboratory test results and PK data from 
Days 1-7 of the prior cohort. 
Part II: Double-blind, placebo-controlled, randomized, multiple ascending dose study for 28 
days of dosing with INDV-2000 in healthy volunteers. The screening period is up to 28 days. 
In each cohort, healthy volunteers will reside at the clinical unit from the evening of Day -1 to 
the morning of Day 8. Doses will be administered twice daily during Days 1-7. Healthy 
volunteers will be discharged after the morning dose administration on Day 8 except in case 
the Investigator judges it appropriate to retain the healthy volunteer to address safety concerns 
until resolution. Healthy volunteers will continue twice daily self-administration of INDV-
2000 at home (except for in-clinic days) from Days 9 through 28. Healthy volunteers will 
return to the clinical unit for outpatient visits on Days 10, 15, 22 and 28 for safety assessments 
and PK samples. The EOS visit will be performed on the morning of Day 35 which is one 
week after the last dose. Male participants will complete a safety phone call 90 days after their 
last dosing day to assess any new pain, swelling or nodular lesions in the scrotum. This may be 
modified based on full evaluation of data from Part I in healthy volunteers. Two cohorts are 
planned, where each cohort will utilize a different dose, and all healthy volunteers within the 
same cohort will receive the same dose. Dose escalation decisions for Part II, Cohorts 1 and 2 
will be based on a blinded review of TEAEs, concomitant medications, vital signs, ECGs, 
clinical laboratory test results and PK data from Days 1-7 of the prior cohort(s). 
Part III: Part III dose determination will follow a blinded review of TEAEs, concomitant 
medications, vital signs, ECGs, clinical laboratory test results, and PK data from Part I, 
Cohorts 1 & 2, Part II, Cohort 1, and Part II, Cohort 2 Days 1-7. This part is an open-label 
study in OUD treatment seeking individuals. The screening period is up to 35 days. After 
screening, if check-in criteria are met, treatment seeking OUD subjects will enter the in-clinic 
portion of the study. First, subjects will initiate a run-in period with SUBOXONE SL film 
daily for 6 days. On Day -1 of the study, subjects must be stabilized on a SUBOXONE SL 
film dose between 8 mg/2 mg and 24 mg/6 mg of buprenorphine/naloxone. If run-in criteria 
are met, each subject will continue dosing with their stabilized dose of SUBOXONE SL film 


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after the run-in period for required in-clinic dosing. Qualifying subjects will continue to Day 1, 
where SUBOXONE SL film dosing alone continues for 2 more days. On Day 3, subjects will 
begin receiving doses of both SUBOXONE SL film and INDV-2000 for 7 days. Starting on 
Day 10, subjects will stop dosing with SUBOXONE SL film and dose with INDV-2000 alone 
for 4 more days and remain in clinic until completion of assessments on Day 14. Rescue 
medications to treat opioid withdrawal signs and symptoms will be allowed in the study based 
on Investigator’s medical judgment. After assessments are completed on Day 14, subjects can 
begin a standard of care treatment for OUD. The EOS visit is scheduled for Day 21. If at any 
stage of the study a subject discontinues, they will be given options for their continued 
treatment for OUD by the clinical facility.
Primary Endpoint(s): 
Part I and Part II: Safety and tolerability of multiple doses of INDV-2000 as determined by 
adverse event reporting (incidence, severity and relatedness of TEAEs; SAEs, events leading 
to discontinuation and deaths) in healthy volunteers. 
Part III: Safety and tolerability following multiple doses of INDV-2000 administered alone 
and with SUBOXONE SL film as determined by adverse event reporting (incidence, severity 
and relatedness of TEAEs; SAEs, events leading to discontinuation and deaths) in an OUD 
treatment seeking population.
Secondary Endpoint(s): 
Part I and Part II: 
 Plasma PK parameters of INDV-2000 after multiple doses 
o Maximum plasma concentration (Cmax), time of maximum plasma concentration (Tmax), 
and area under the plasma concentration-time curve (AUC0-24 or 0-12) of INDV-2000 
following dosing on Days 1 and 7 (Part I) and Days 1, 7 and 28 (Part II)
Exploratory Endpoints: 


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Safety Assessments 
Part I, Part II and Part III: 
The following clinical safety parameters will be assessed for means, trends and/or changes 
from baseline. Clinically significant findings for the following clinical safety assessments will 
be reported as adverse events: 
 laboratory results 
 electrocardiogram (ECG) findings 
 vital sign measures 
 physical examination 
 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
 
 
 


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STUDY SCHEMATIC 
Figure 1 
Study Schematic 
 
 
 
 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL: INDV-2000-102 ................................................................1 
CLINICAL PROTOCOL SIGNATURE PAGE ........................................................................2 
STUDY PERSONNEL INFORMATION .................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ....................................................4 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...............................................6 
SYNOPSIS .................................................................................................................................7 
STUDY SCHEMATIC ............................................................................................................13 
TABLE OF CONTENTS .........................................................................................................14 
LIST OF IN-TEXT TABLES ..................................................................................................18 
LIST OF IN-TEXT FIGURES.................................................................................................18 
LIST OF ABBREVIATIONS ..................................................................................................19 
1 
INTRODUCTION AND RATIONALE ..........................................................................21 
1.1 
Background and Introduction ................................................................................21 
1.2 
Study Rationale ......................................................................................................22 
1.2.1 
Dose Rationale .............................................................................................22 
1.3 
Nonclinical Pharmacology .....................................................................................23 
1.4 
Risk-Benefit Assessment .......................................................................................23 
2 
STUDY OBJECTIVES ....................................................................................................25 
2.1 
Primary ...................................................................................................................25 
2.2 
Secondary ...............................................................................................................25 
2.3 
Exploratory ............................................................................................................25 
3 
STUDY ENDPOINTS .....................................................................................................26 
3.1 
Primary ...................................................................................................................26 
3.2 
Secondary ...............................................................................................................26 
3.3 
Exploratory ............................................................................................................26 
3.3.1.1 
Safety Assessments ............................................................................27 
4 
STUDY PLAN .................................................................................................................28 
4.1 
Study Design ..........................................................................................................28 
4.2 
Schedule of Events .................................................................................................29 
4.3 
Duration of Study ...................................................................................................29 
5 
STUDY POPULATION SELECTION ...........................................................................30 
5.1 
Number of Subjects................................................................................................30 
5.2 
Inclusion Criteria ...................................................................................................30 
5.3 
Exclusion Criteria ..................................................................................................30 
5.4 
Check-In and Run-In Assessment Criteria ............................................................32 
5.5 
Deviation from Inclusion/Exclusion Criteria .........................................................33 
6 
STUDY CONDUCT ........................................................................................................34 


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6.1 
Subject Enrolment ..................................................................................................34 
6.2 
Screen Failure ........................................................................................................34 
6.3 
Run-in Failure ........................................................................................................34 
6.4 
Subject Completion ................................................................................................34 
6.5 
Dose Escalation and Stopping Criteria ..................................................................34 
6.5.1.1 
Part I and II - Individual Stopping Criteria ........................................35 
6.5.1.2 
Part I and II – Cohort Stopping Criteria.............................................36 
6.5.1.3 
Part III - Individual Stopping Criteria ................................................36 
6.5.1.4 
Study Stopping Criteria (Parts I, II and III) .......................................37 
6.5.2 
Suicidal Ideation and Behaviour ..................................................................37 
6.6 
Subject Withdrawal from Study .............................................................................37 
6.6.1 
Subject Withdrawal of Consent ...................................................................38 
6.6.2 
Subjects Lost to Follow-up ..........................................................................38 
7 
STUDY SUSPENSION OR TERMINATION ................................................................39 
8 
DESCRIPTION OF STUDY PROCEDURES ................................................................40 
8.1 
Informed Consent...................................................................................................40 
8.2 
Demographics, Baseline Characteristics and Medical History ..............................40 
8.3 
Physical Examination.............................................................................................40 
8.4 
Vital Signs ..............................................................................................................41 
8.5 
12-Lead Electrocardiograms ..................................................................................41 
8.6 
26-Hour Holter Monitoring....................................................................................42 
8.7 
Clinical Laboratory Tests .......................................................................................42 
8.7.1 
Sample Collection, Storage and Shipping ...................................................43 
8.8 
Columbia-Suicide Severity Rating Scale ...............................................................44 
8.9 
Pharmacokinetic Assessments ...............................................................................44 
8.9.1 
Plasma Samples for Pharmacokinetic Analysis ...........................................44 
8.9.2 
Sample Bioanalysis ......................................................................................44 
8.10 
Pharmacodynamic Outcomes.................................................................................45 
8.10.1 
Part I, Part II and Part III .............................................................................45 
8.10.1.1 
 ............................................45 
8.10.2 
Part III Only .................................................................................................45 
8.10.2.1 
45 
8.10.2.2 
 ......................................45 
8.10.2.3 
 ...................................46 
8.10.2.4 
 .......................................................46 
8.10.2.5 
 ..........................................................46 
8.11 
Appropriateness of Measurements .........................................................................47 
8.12 
Protocol Deviations ................................................................................................47 
8.13 
Order of Procedures ...............................................................................................47 


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9 
STUDY DRUG MANAGEMENT ..................................................................................48 
9.1 
Description .............................................................................................................48 
9.1.1 
Drug Manufacturer.......................................................................................48 
9.1.2 
Placebo .........................................................................................................48 
9.1.3 
Blinding and Randomization .......................................................................48 
9.1.4 
Parts I and II .................................................................................................50 
9.2 
Packaging, Labelling and Storage ..........................................................................51 
9.2.1 
Packaging and Labelling ..............................................................................51 
9.2.2 
Storage Conditions .......................................................................................51 
9.2.3 
Drug Shipment .............................................................................................51 
9.3 
Drug Administration ..............................................................................................51 
9.3.1 
Part III ..........................................................................................................52 
9.4 
Accountability ........................................................................................................52 
9.5 
Reporting Product Complaints ...............................................................................52 
9.6 
Prior and Concomitant Therapies ..........................................................................53 
9.6.1 
Permitted Concomitant Therapies................................................................53 
9.6.2 
Prohibited Concomitant Therapies ..............................................................53 
9.6.3 
Lifestyle Restrictions ...................................................................................54 
9.6.3.1 
Fluid and Food Intake (Parts I, II and III) ..........................................54 
9.6.3.2 
Subject Activity Restrictions (Parts I, II and III) ...............................54 
9.6.3.3 
Caffeine, Alcohol and Tobacco Restrictions (Parts I and II, but Not 
Part III) ...............................................................................................54 
9.7 
Compliance ............................................................................................................54 
10 ADVERSE EVENTS .......................................................................................................55 
10.1 
Assessment of Adverse Events ..............................................................................56 
10.1.1 
Time Period for Collecting Adverse Events ................................................56 
10.1.2 
Assessment of Intensity ...............................................................................57 
10.1.3 
Assessment of Causality ..............................................................................57 
10.1.4 
Clinical Laboratory Changes .......................................................................58 
11 SERIOUS ADVERSE EVENTS .....................................................................................59 
11.1 
Documenting Serious Adverse Events...................................................................60 
11.2 
Reporting Serious Adverse Events ........................................................................60 
11.2.1 
Investigator Reporting of Serious Adverse Events ......................................60 
11.2.2 
Regulatory Reporting Requirements for Serious Adverse Events ...............61 
11.2.3 
Overdose ......................................................................................................61 
12 PREGNANCY .................................................................................................................62 
12.1 
Action to be Taken if Pregnancy Occurs in a Female Subject ..............................62 
12.2 
Action to be Taken if Pregnancy Occurs in a Female Partner ...............................62 


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13 DATA MANAGEMENT.................................................................................................64 
13.1 
Data Collection and Management ..........................................................................64 
13.1.1 
Database Quality Assurance ........................................................................64 
13.1.2 
Source Documents .......................................................................................64 
14 STATISTICS ...................................................................................................................65 
14.1 
General Procedures ................................................................................................65 
14.2 
Sample Size ............................................................................................................65 
14.3 
Analysis Populations ..............................................................................................65 
14.3.1 
Safety Population .........................................................................................65 
14.3.2 
Run-In Safety Population .............................................................................66 
14.3.3 
Pharmacokinetic Population ........................................................................66 
14.4 
Demographic and Baseline Characteristics ...........................................................66 
14.5 
Extent of Exposure .................................................................................................66 
14.6 
Prior and Concomitant Medications ......................................................................66 
14.7 
Study Endpoints .....................................................................................................66 
14.7.1 
Primary Endpoints .......................................................................................66 
14.7.2 
Secondary Endpoints ...................................................................................66 
14.7.3 
Exploratory Endpoints .................................................................................67 
14.8 
Pharmacokinetic Analysis ......................................................................................68 
14.9 
Safety Assessments ................................................................................................69 
14.9.1 
Treatment-Emergent Adverse Events (TEAEs) ...........................................69 
14.9.2 
Laboratory Evaluations ................................................................................69 
14.9.3 
Vital Signs ....................................................................................................69 
14.9.4 
12-Lead Electrocardiogram .........................................................................70 
14.9.5 
Physical Examination...................................................................................70 
14.9.6 
Columbia-Suicide Severity Rating Scale .....................................................70 
14.10 Pharmacodynamic Outcomes.................................................................................70 
14.11 Interim Analysis .....................................................................................................71 
14.12 Handling of Missing Data ......................................................................................71 
15 ETHICS AND RESPONSIBILITIES ..............................................................................71 
15.1 
Good Clinical Practice ...........................................................................................71 
15.2 
Data Review and Safety Committee ......................................................................71 
15.3 
Institutional Review Board ....................................................................................71 
15.4 
Informed Consent...................................................................................................72 
15.5 
Records Management.............................................................................................72 
16 AUDITING AND MONITORING..................................................................................74 
17 AMENDMENTS .............................................................................................................76 
18 STUDY REPORTS AND PUBLICATIONS ..................................................................77 


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19 STUDY TERMINATION ...............................................................................................78 
20 CONFIDENTIALITY......................................................................................................79 
21 REFERENCES ................................................................................................................80 
22 APPENDICES .................................................................................................................82 
22.1 
APPENDIX 1 – Schedule of Events Part I ............................................................82 
22.2 
APPENDIX 2 – Schedule of Events Part II ...........................................................84 
22.3 
APPENDIX 3 – Schedule of Events Part III .........................................................87 
22.3.1 
Part III - Screening and SUBOXONE SL Film Run-In ...............................87 
22.3.2 
Part III – Schedule of Events .......................................................................89 
22.4 
APPENDIX 4 – Liver Safety .................................................................................91 
22.5 
APPENDIX 5 –Plasma PK Sampling Windows ...................................................94 
22.6 
APPENDIX 6- Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials ...................................98 
I. 
INTRODUCTION ...............................................................................................101 
II. 
BACKGROUND .................................................................................................102 
III. 
TOXICITY GRADING SCALE TABLES .........................................................102 
IV. 
REFERENCES ....................................................................................................108 
 
List of In-Text Tables 
Table 1 
List of Laboratory Tests ...............................................................................43 
Table 2 
Part I and Part II Multiple Ascending Study Drug Dosing: Projected Doses51 
 
List of In-Text Figures 
Figure 1 
 Study Schematic..........................................................................................13 
 


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List of Abbreviations 
ADME 
AE
Absorption, distribution, metabolism and excretion 
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC 
BID 
BMI
Area under the drug plasma concentration versus time curve 
Twice-daily 
Body mass index
CDMS
Clinical Data Management System
cGMP 
CHF
Current Good Manufacturing Practices 
Congestive Heart Failure
Cmax 
CNS
Maximum plasma concentration 
Central Nervous System
CPK
Creatine phosphokinase
CRF
Case Report Form
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DRSC
Data Review and Safety Committee
ECG
Electrocardiogram
eCRF 
EOS 
ET
Electronic Case Report Form 
End of Study 
Early Termination
FDA
Food and Drug Administration
FIH 
FR 
FSH
First-in-human 
Fixed Ration 
Follicle-stimulating Hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
Hepatitis B surface Antigen
hERG 
HIV
Human Ether-a-Go-go Related Gene 
Human immunosufficiency virus
IB
Investigator Brochure
IC50
Half-maximal inhibitory concentration
ICF
Informed Consent
ICH 
ID
International Committee on Harmonisation 
Identification
IgM
Immunoglobulin M
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
ISF
Investigator Site File
LC
Locus coeruleus
MedDRA
Medical Dictionary for Regulatory Activities


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MTD
maximum well-tolerated
NOAEL
No Observed Adverse Effect Level
OUD
Opioid use disorder
OX1
Orexin-1
OX2
Orexin-2
OX1R
Orexin-1 receptor
OX2R
Orexin-2 receptor
PD 
PI
Pharmacodynamic(s) 
Principal Investigator
pIC50
Negative log of IC50
PK 
PR
Pharmacokinetic(s) 
Progressive Ration
QA 
QD
Quality Assurance 
Once-daily
QTcF
QT interval corrected with Fridericia’s formula
SAD
Single ascending dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBP 
SD
Systolic blood pressure 
Standard Deviation
SL
Sublingual
SOC
System Organ Class
SOP
Standard Operating Procedures
SUSAR
Suspected unexpected serious adverse reaction
Tmax
Time to reach maximum (peak) plasma concentration
TEAE
Treatment-Emergent Adverse Events
TESAE 
UDS 
ULN
Treatment-Emergent Serious Adverse Events 
Urine drug screen 
Upper Limit of Normal


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1 
INTRODUCTION AND RATIONALE 
1.1 
Background and Introduction 
Orexin-A and Orexin-B are neuropeptides, also known as hypocretins, that regulate arousal, 
wakefulness, feeding and motivation (De Lecea 1998, Sakurai 1998). Orexin-A and Orexin-B 
are produced from a precursor polypeptide, prepro-orexin, by enzymatic cleavage. The orexin 
peptides are agonists of 2 G protein-coupled receptors (GPCRs): the Orexin-1 receptor (OX1R) 
and Orexin-2 receptor (OX2R). The OX1R has much higher affinity for Orexin-A compared to 
Orexin-B, whereas these 2 neuropeptides are equipotent at the OX2R (Sakurai 1998). Orexin-A 
is completely conserved across several mammalian species including human, rat and dog. 
In humans, the OX1R is expressed predominantly in the brain (HCRTR1 2009) and in rat 
differential expression of the Orexin-1 and -2 receptors across brain regions has been 
demonstrated (Trivedi 1998, Marcus 2001). The OX1 and OX2 receptors are highly conserved 
across mammalian species with 94% identity at the amino acid level between humans and rats 
(Sakurai 1998). A limited number of coding and non-coding genetic variants of the OX1R have 
been identified but no clear functional impact or linkage to disease has been demonstrated 
(Thompson 2014). Both OX1R and OX2R are coupled to Gq/11 proteins that activate the 
Phospholipase C/Inositol Phosphate IP3 pathway, leading to a transient increase of intracellular 
calcium (Kukkonen 2013). 
Studies in rats have shown that prepro-orexin is expressed exclusively in the lateral 
hypothalamic (LH) region and that orexin neurons project to multiple brain regions including the 
paraventricular nucleus of the hypothalamus (PVH), the amygdala, the locus coeruleus (LC), 
ventral tegmental area (VTA) and the nucleus accumbens (NAcc) (Peyron 1998). The orexin 
neurons in the lateral hypothalamus become activated by cues associated with the reward system 
such as drugs and food (Harris 2005). Stimulation of rat LC neurons with Orexin-A causes 
membrane depolarization and increased action potential firing, leading to increased neuronal 
excitability, an effect blocked by SB334867, an OX1R antagonist compound (Soffin 2002). The 
number of Orexin-A-producing neurons are increased in the brains of individuals with heroin 
dependence and in mice after long-term administration of morphine (Thannickal 2018). 
Antagonism of the OX1R inhibits addiction-related behaviours in rodent nonclinical models 
including self-administration, relapse to drug-seeking and withdrawal (Mahler 2012, Zarrabian 
2018). Hence it is hypothesized that OX1R antagonists should show clinical benefit in the 
treatment of substance use disorders including opioid use disorder (OUD) by reducing craving, 
relapse and symptoms of withdrawal. 
In addition to its role in addiction, Orexin-A has been shown to induce panic and anxiety-like 
behaviours in the rat which can be inhibited by OX1R antagonists (Johnson 2010, Bonaventure 
2017). The OX1R may therefore play a role in anxiety. 


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1.2 
Study Rationale 
1.2.1 
Dose Rationale 


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1.3 
Nonclinical Pharmacology 
1.4 
Risk-Benefit Assessment 


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2 
STUDY OBJECTIVES 
2.1 
Primary 
The primary objectives for the study are: 
Part I and II 
 Assess safety and tolerability of INDV-2000 following repeated doses of INDV-2000 in 
healthy volunteers. 
Part III 
 Assess the safety and tolerability following repeated doses of INDV-2000 administered alone 
and with SUBOXONE sublingual (SL) film in an OUD treatment seeking population. 
2.2 
Secondary 
The secondary objectives for the study are: 
Part I and II 
 Characterize the pharmacokinetic (PK) profile following multiple doses of INDV-2000. 
 
2.3 
Exploratory 


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3 
STUDY ENDPOINTS 
3.1 
Primary 
Part I and Part II: Safety and tolerability of multiple doses of INDV-2000 as determined by 
adverse event reporting (incidence, severity and relatedness of TEAEs; SAEs; events leading to 
discontinuation and death) in healthy volunteers. 
Part III: Safety and tolerability following multiple doses of INDV-2000 administered alone and 
with SUBOXONE SL film as determined by adverse event reporting (incidence, severity and 
relatedness of TEAEs; SAEs; events leading to discontinuation and death) in an OUD treatment 
seeking population 
3.2 
Secondary 
Part I and Part II: 
 Plasma PK parameters of INDV-2000 after multiple doses 
o Maximum plasma concentration (Cmax), time of maximum plasma concentration (Tmax), 
and area under the plasma concentration-time curve (AUC0-24 or 0-12) of INDV-2000 
following dosing on Days 1 and 7 (Part I) and Days 1, 7 and 28 (Part  II) 
 
3.3 
Exploratory 


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3.3.1.1 
Safety Assessments 
Part I, Part II and Part III: 
The following clinical safety parameters will be assessed for means, trends and/or changes from 
baseline. Clinically significant findings for the following clinical safety assessments will be 
reported as adverse events: 
 laboratory results 
 electrocardiogram (ECG) findings 
 vital sign measures 
 physical examination 
 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
 


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4 
STUDY PLAN 
4.1 
Study Design 
The study will be conducted in 3 parts: 
Part I: Double-blind, placebo-controlled, randomized, multiple ascending dose study for 7 days 
of dosing with INDV-2000 in healthy volunteers. The screening period is up to 28 days. In each 
cohort, healthy volunteers will reside at the clinical unit from the evening of Day -1 to the 
morning of Day 8. In Cohort 1, doses will be administered once daily in the morning of Days 1-
7. In Cohort 2, doses will be administered twice daily during Days 1-7. Healthy volunteers will 
be discharged on Day 8 except in the case the Investigator judges it appropriate to retain the 
healthy volunteer to address safety concerns until resolution. The EOS visit will be performed on 
Day 14 which is one week after the last dose. Male participants will complete a safety phone call 
90 days after their last dosing day to assess any new pain, swelling or nodular lesions in the 
scrotum.  Two cohorts are planned, where each cohort will utilize a different dose, and all 
healthy volunteers within the same cohort will receive the same dose. The dose escalation 
decision for Part I, Cohort 2 will be based on a blinded review of TEAEs, concomitant 
medications, vital signs, ECGs, clinical laboratory test results and PK data from Days 1-7 of the 
prior cohort. 
Part II: Double-blind, placebo-controlled, randomized, multiple ascending dose study for 28 
days of dosing with INDV-2000 in healthy volunteers. The screening period is up to 28 days. In 
each cohort, healthy volunteers will reside at the clinical unit from the evening of Day -1 to the 
morning of Day 8. Doses will be administered twice daily during Days 1-7. Healthy volunteers 
will be discharged after the morning dose administration on Day 8 except in case the Investigator 
judges it appropriate to retain the healthy volunteer to address safety concerns until resolution. 
Healthy volunteers will continue twice daily self-administration of INDV-2000 at home (except 
for in-clinic days) from Days 9 through 28. Healthy volunteers will return to the clinical unit for 
outpatient visits on Days 10, 15, 22 and 28 for safety assessments and PK samples. The EOS 
visit will be performed on the morning of Day 35 which is one week after the last dose. Male 
participants will complete a safety phone call 90 days after their last dosing day to assess any 
new pain, swelling or nodular lesions in the scrotum.  This may be modified based on full 
evaluation of data from Part I in healthy volunteers. Two cohorts are planned, where each cohort 
will utilize a different dose, and all healthy volunteers within the same cohort will receive the 
same dose. Dose escalation decisions for Part II, Cohorts 1 and 2 will be based on a blinded 
review of TEAEs, concomitant medications, vital signs, ECGs, clinical laboratory test results and 
PK data from Days 1-7 of the prior cohort(s).  
Part III: Part III dose determination will follow a blinded review of TEAEs, concomitant 
medications, vital signs, ECGs, clinical laboratory test results, and PK data from Part I, Cohorts 
1 & 2, Part II, Cohort 1, and Part II, Cohort 2 Days 1-7. This part is an open-label study in OUD 
treatment seeking individuals. The screening period is up to 35 days. After screening, if check-in 
criteria are met, treatment seeking OUD subjects will enter the in-clinic portion of the study. 
First, subjects will initiate a run-in period with SUBOXONE SL film daily for 6 days. On Day -1 
of the study, subjects must be stabilized on a SUBOXONE SL film dose between 8 mg/2 mg and 


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24 mg/6 mg of buprenorphine/naloxone. If run-in criteria are met, each subject will continue 
dosing with their stabilized dose of SUBOXONE SL film after the run-in period for required in-
clinic dosing. Qualifying subjects will continue to Day 1, where SUBOXONE SL film dosing 
alone continues for 2 more days. On Day 3, subjects will begin receiving doses of both 
SUBOXONE SL film and INDV-2000 for 7 days. Starting on Day 10, subjects will stop dosing 
with SUBOXONE SL film and dose with INDV-2000 alone for 4 more days and remain in clinic 
until completion of assessments on Day 14. Rescue medications to treat opioid withdrawal signs 
and symptoms will be allowed in the study based on Investigator’s medical judgment. After 
assessments are completed on Day 14, subjects can begin a standard of care treatment for OUD. 
The EOS visit is scheduled for Day 21. If at any stage of the study a subject discontinues, they 
will be given options for their continued treatment for OUD by the clinical facility. 
A schematic depicting the study design is in Figure 1. 
4.2 
Schedule of Events 
A complete list of procedures and assessments are located in the Schedule of Events tables in 
Section 22.1, Appendix 1 for Part I, Section 22.2, Appendix 2 for Part II and Section 22.3, 
Appendix 3 for Part III of the study. 
4.3 
Duration of Study 
 Part I: The study will be an INDV-2000 multiple ascending dose study. Total study duration per 
cohort inclusive of Screening through the EOS visit is approximately 42 days.  
Part II: The study will be an INDV-2000 multiple ascending dose study. Total study duration per 
cohort inclusive of Screening through the EOS visit is approximately 63 days. 
Part III: This study will be open-label dosing of INDV-2000. Total study duration inclusive of 
Screening through the EOS visit is approximately 56 days. 
For study Parts I and II, male participants will complete a safety phone call 90 days after their 
last dosing day to assess any new pain, swelling or nodular lesions in the scrotum. 


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5 
STUDY POPULATION SELECTION 
5.1 
Number of Subjects 
Part I (2 cohorts) and Part II (2 cohorts): Each cohort will be composed of 12 healthy volunteers 
(9 receiving active and 3 placebo). A total of 48 healthy male and female volunteers are planned 
to participate in both parts. Study subjects who are randomized but do not receive IMP will be 
replaced. 
Part III: A single group of up to 16 treatment seeking subjects with OUD. 
5.2 
Inclusion Criteria 
In order to participate in the study, subjects must meet the following criteria: 
1. Able to verbalize understanding of the consent form, able to provide written informed 
consent, and verbalize willingness to complete study procedures, be able to comply with 
protocol requirements, rules and regulations of study site, and be likely to complete all the 
study interventions. 
2. Males, or females of non-childbearing potential; 
a. Females of non-childbearing potential are considered women who: 
 Do not have a uterus, or 
 Are surgically sterile (example: has undergone complete hysterectomy, bilateral 
oophorectomy, or tubal ligation), or 
 Have permanent cessation of ovarian function due to ovarian failure or surgical removal 
of the ovaries, or 
 Are post-menopausal as defined by 12 months or more of spontaneous amenorrhea as 
confirmed by a follicle-stimulating hormone (FSH) >30 mIU/mL 
Part I and II only: 
3. Male or female who is healthy as determined by a medical evaluation. 
4. Between 18 and 55 years of age inclusive. 
5. Body mass index (BMI) within 18.0 to 32.0 kg/m2, inclusive (minimum weight of at least 
50.0 kg at Screening). 
Part III only: 
6. Male or female seeking treatment for OUD with a diagnosis of moderate or severe OUD by 
DSM-5 criteria. 
7. Between 18 and 65 years of age inclusive. 
8. BMI within 18.0 to 35.0 kg/m2, inclusive (minimum weight of at least 50.0 kg at Screening). 
5.3 
Exclusion Criteria 
Subjects must not meet any of the following criteria: 
1. Have a medical history of clinically significant neurological, cardiovascular, renal, hepatic, 
chronic respiratory or gastrointestinal disease, or psychiatric disorder as judged by an 
Investigator. 


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2. Have clinically significant abnormal biochemistry, haematology or urinalysis results as 
judged by an Investigator or medically responsible physician. (Refer to additional laboratory 
exclusion criteria for Part III subjects in Exclusion 28). 
3. Have a history of narcolepsy or other significant sleep disorders. 
4. Have disorders that may interfere with drug absorption, distribution, metabolism and 
excretion (ADME) processes. 
5. Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or 
Hepatitis C Antibody (HCVAb). 
6. Serious cardiac illness or other cardiac assessments including, but not limited to: 
a. Uncontrolled arrhythmias. 
b. History of congestive heart failure (CHF). 
c. Myocardial infarction <6 months from receipt of first dose of IMP 
d. Uncontrolled symptomatic angina 
e. QTcF >450 msec for males and >470 msec for females or history of prolonged QT 
syndrome. 
7. Current active hepatic or biliary disease, including subjects with cholecystectomy <90 days 
prior to Screening. 
8. Concurrent treatment or treatment with an investigational drug, or participation in any other 
clinical study within 30 days prior to the signing the informed consent form. 
9. History of suicidal ideation within 30 days prior to providing written informed consent as 
evidenced by answering "yes' to questions 4 or 5 on the suicidal ideation portion of the 
C-SSRS completed at the Screening Visit or history of a suicide attempt (per the C-SSRS) in 
the 6 months prior to informed consent. 
10. Pregnant or lactating females. 
11. Any consumption of food or drink containing poppy seeds, grapefruit or Seville oranges 
within 7 days prior to the IMP administration. 
12. Blood donation of greater than 500 mL within 56 days or plasma donation within 7 days of 
screening; clinically significant anaemia or low haemoglobin (<11 g/dL for females, <12 
g/dL for males). 
13. Treatment with any known drugs that are moderate or strong inhibitors/inducers of 
cytochrome P450 (CYP) 3A4 within 30 days prior to first dose of IMP. 
14. Known allergy or hypersensitivity to IMP or its excipients. 
15. Any condition that, in the opinion of an Investigator or medically responsible physician, 
would interfere with evaluation of the IMP or interpretation of subject safety or study results. 
16. Affiliated with, or a family member of, site staff directly involved in the study, or anyone 
with a financial interest in the outcome of the study. 
17. Subjects who are unable, in the opinion of an Investigator or medically responsible 
physician, to comply fully with the study requirements. 
18. Current incarceration or pending incarceration/legal action that could prevent participation or 
compliance in the study. 
 
Part I and II only: 
19. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 
unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine). 
20. Positive test result for alcohol and/or any drugs of abuse at screening 


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21. Have a blood pressure reading outside of the following range: Systolic <86 or >149 mmHg; 
Diastolic <50 or >94 mmHg 
22. Current smokers and those who have smoked within the last 90 days. Current users of e-
cigarettes and nicotine replacement products, and those who have used these products within 
the last 90 days. 
23. Healthy volunteers who are taking, or have taken, any prescribed or over-the-counter drugs 
(other than 2 g per day acetaminophen, hormone replacement therapy [HRT]) or herbal 
remedies in the 14 days before IMP administration. Exceptions may apply on a case-by-case 
basis if considered not to interfere with the objectives of the study, as agreed by an 
Investigator and Sponsor's Medical Monitor. 
Part III only: 
24. Regular alcohol consumption in males >27 units per week and females >20 units per week (1 
unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine). 
25. Current substance use disorder, as defined by DSM-5 criteria, with any substances other than 
opioids, tobacco, cannabis, or alcohol, or dependence with any substance that would interfere 
with the completion of the study by judgment of the Investigator or medically responsible 
physician. 
26. Current history of alcohol withdrawal within one year prior to screening. 
27. Have a blood pressure reading outside of the following range: Systolic <86 or >159 mmHg; 
Diastolic <50 or >99 mmHg. Investigator should rule out acute changes resulting from opioid 
withdrawal. 
28. Has total bilirubin ≥1.5 × upper limit of normal (ULN) (with direct bilirubin >1.3 mg/dL), 
alanine aminotransferase (ALT) ≥3 × ULN, aspartate aminotransferase (AST) ≥3 × ULN, 
serum creatinine >2 × ULN, or international normalized ratio (INR) >1.5 × ULN at 
Screening). 
29. Received medication-assisted treatment for OUD (e.g., methadone, buprenorphine) in the 30 
days prior to providing written informed consent. 
30. Received any prior treatment with a buprenorphine implant or injection. 
31. Treatment for OUD required by court order. 
5.4 
Check-In and Run-In Assessment Criteria 
Upon passing screening and meeting inclusion and not meeting exclusion criteria, the subject 
will present to the clinic for admission. 
For Part I and Part II, the following criteria must be met at Day -1 for the healthy volunteer to 
be checked into the clinic: 
1. Females must have a negative urine pregnancy test. 
2. Must not have a QTcF >450 msec for males and >470 msec for females. 
3. Must have a negative result obtained from the urine drug screen (UDS) and the alcohol test 
(urine ethanol). 
a. Healthy volunteers who have a positive result for alcohol will be asked to refrain from 
alcohol and return the next day for retest. This may only occur once. 
4. Must have a negative polymerase chain reaction (PCR) test result for COVID-19. 


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If any of these criteria are not met, the subject will not be enrolled into the study. 
For Part III, subjects must meet the following criteria in order to be checked into the clinic on 
Day -6: 
1. Females must have a negative urine pregnancy test. 
2. Must have a negative PCR test result for COVID-19. 
For Part III, subjects must meet the following criteria in order to complete run-in, and proceed 
into the study on Day -1: 
1. Tolerating daily dose of SUBOXONE SL film between 8mg/2mg – 24mg/6mg (inclusive). 
2. COWS score of ≤ 12. 
 
If any of these criteria are not met, the subject will not be enrolled. 
 
5.5 
Deviation from Inclusion/Exclusion 
Criteria 
This study is intended to be conducted as described in this protocol. Waivers from inclusion and 
exclusion criteria are not allowed because they have the potential to jeopardize subject safety, the 
scientific integrity of the study or regulatory acceptability of the data. Indivior does not grant 
waivers to the protocol-defined inclusion and exclusion criteria, and strict adherence to these 
criteria as outlined in the protocol is essential.  
The Principal Investigator (PI), sub-Investigator or suitably qualified designee will be 
responsible for identifying, documenting and reporting all deviations, which are defined as 
isolated occurrences involving a procedure that did not follow the study protocol or study-
specific procedure. In the event of a major deviation from the protocol due to an emergency, 
accident or mistake (e.g., eligibility or dosing errors), the PI, sub-Investigator or suitably 
qualified designee must contact the Indivior Medical Monitor at the earliest possible time by 
telephone. This will allow an early joint decision regarding the subject’s continuation in the 
study. This decision will be documented by the Investigator and the Sponsor. Deviations will be 
reported as required to the Institutional Review Board (IRB) per their reporting process and 
criteria, and in the final study report. 


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6 
STUDY CONDUCT 
6.1 
Subject Enrolment 
Study participation begins once written informed consent is obtained; a subject identification 
(ID) number is then assigned. The subject ID will be used to identify the subject during the 
screening process and throughout study participation. A subject is considered enrolled once 
randomized in Part I or Part II, and in Part III, if Day -1 run-in assessment criteria are met. 
The Investigator is responsible for maintaining a master list (i.e., a subject ID list) of all 
consented subjects. This document will be reviewed by Indivior or designated representative for 
accuracy and completeness. Ineligible subjects, as defined by the protocol-specific inclusion and 
exclusion criteria, should not receive IMP and should be documented as screen failures. 
6.2 
Screen Failure 
A subject will be considered a screen failure if written informed consent is obtained, but the 
subject did not meet inclusion criteria or met one or more exclusion criteria. The study site will 
keep a Screening Log documenting subjects who have signed an informed consent. Screen 
failure reasons will be documented on the Screening Log as well as collected in the electronic 
case report form (eCRF). 
6.3 
Run-in Failure 
In Part III only, a subject will be a run-in failure if written informed consent is obtained, the 
subject did meet inclusion criteria and did not meet exclusion criteria, however did not move past 
the run-in period of the study, and did not receive IMP (see Section 9 for the definition of 
“IMP”). Run-in failures will be documented on the Screening Log and the reason for run-in 
failure will be collected in the eCRF. 
6.4 
Subject Completion 
For Parts I and II, a completed subject is one that completes the EOS visit. The end of the study 
is defined as the last subject’s last visit.  
For Part III, a completed subject is one who receives all scheduled doses of INDV-2000 and 
completes Day 14 safety assessments. 
6.5 
Dose Escalation and Stopping Criteria 
The Data Review and Safety Committee (DRSC) will review blinded data from cohorts in Part I 
and Part II of the study and will determine if the dose can be escalated as planned, or 
alternatively, if any stopping criteria have been met. See Section 15.2 


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Dose escalation will be dependent upon observed safety, tolerability and PK, but the increase 
from one cohort to the next will not exceed 2-fold in dose. In no case will the maximum daily 
drug exposure exceed that observed at the NOAEL in the most sensitive toxicology species. 
The DRSC will also review individual subjects as needed to determine if the individual’s 
participation should be stopped based on emerging safety and PK data. 
 
6.5.1.1 
Part I and II - Individual Stopping Criteria 
If the following criteria are met at any point during Parts I or II, the affected individual’s dosing 
will be paused to allow unblinded review of affected individuals by the DRSC before continuing 
dosing. A healthy volunteer will be discontinued if any of the criteria listed below are confirmed: 
AEs: 
 The healthy volunteer experiences an SAE that is not clearly unrelated to the IMP. 
Laboratory Abnormalities: 
The healthy volunteer has an abnormality of one or both of the following parameters, whose 
temporal relationship to the IMP makes causality plausible, confirmed on repeat testing: 
 Serum ALT or AST >3 times the ULN 
 Total serum bilirubin >2 times the ULN (>35% direct bilirubin). 
Vital Signs: 
The healthy volunteer fulfils one or both of the following vital sign criteria based on the mean of 
triplicate measures (≥ 1 minute apart), that will be completed once the first blood pressure 
reading is outside the accepted range: 
 Systolic blood pressure (SBP) <85 or >170 mmHg and/or change from Baseline >30 mmHg 
sustained for at least 1 hr (measures repeated every 15 min) 
 Diastolic blood pressure (DBP) <45 or >105 mmHg and/or change from Baseline >30 mmHg 
sustained for at least 1 hr (measures repeated every 15 min) 
ECG Criteria: 
The healthy volunteer fulfils the following ECG criteria based on the mean of triplicate measures 
(≥ 1 minute apart), that will be completed once the first ECG demonstrates a prolonged interval: 
 QTcF ≥500 msec or uncorrected QT interval of >600 msec. 
Plasma INDV-2000 Concentrations 


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6.5.1.2 
Part I and II – Cohort Stopping Criteria 
The study will be paused pending evaluation of all available data by the DRSC if any of the 
criteria listed below are fulfilled for an individual dosing cohort. The DRSC will conduct a 
review of unblinded data of the affected individuals to determine if any additional safety 
monitoring or changes to the protocol are required. 
AEs: 
 Three healthy volunteers experience a similar severe AE that is not clearly unrelated to the 
IMP, or 
 Two healthy volunteers experience a similar SAE that is not clearly unrelated to the IMP. 
Laboratory Abnormalities: 
Two healthy volunteers with an abnormality of one or both of the following parameters, whose 
temporal relationship to the IMP makes causality plausible, confirmed on repeat testing: 
 Serum ALT or AST >3 times the ULN. 
 Total serum bilirubin >2 times the ULN (>35% direct bilirubin). 
Vital Signs: 
Two healthy volunteers fulfil one or both of the following vital sign criteria based on the mean of 
triplicate measures (≥1 minute apart), that will be completed once the first blood pressure 
reading is outside the accepted range: 
 SBP <85 or >170 mmHg and/or change from Baseline >30 mmHg sustained for at least 1 hr 
(measures repeated every 15 min) 
 DBP <45 or >105 mmHg and/or change from Baseline >30 mmHg sustained for at least 1 hr 
(measures repeated every 15 min) 
ECG Criteria: 
Two healthy volunteers fulfil the following ECG criteria based on the mean of triplicate 
measures (≥ 1 minute apart), that will be completed once the first ECG demonstrates a prolonged 
interval: 
 QTcF ≥500 msec or uncorrected QT interval of >600 msec. 
6.5.1.3 
Part III - Individual Stopping Criteria 
A subject will be discontinued if any of the criteria listed below are fulfilled: 
AEs: 
 The subject experiences an SAE that is not clearly unrelated to the IMP. 
Laboratory Abnormalities: 
The subject has an abnormality of one or both of the following parameters, whose temporal 
relationship to the IMP makes causality feasible, confirmed on repeat testing: 


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 Serum ALT or AST >5 times the ULN or 2-fold above baseline if baseline is ≥ 1.5 times 
ULN. 
 Total serum bilirubin >2 times the ULN (>35% direct bilirubin). 
ECG Criteria: 
The subject fulfils the following ECG criteria based on the mean of triplicate measures (≥ 1 
minute apart), completed once the first ECG demonstrates a prolonged interval: 
 QTcF ≥500 msec or uncorrected QT interval of >600 msec. 
 
If the preceding criteria are met, the DRSC will conduct a review of the affected individuals to 
determine if any additional safety monitoring or changes to the protocol are required. 
6.5.1.4 
Study Stopping Criteria (Parts I, II and III) 
If the following criteria are met at any point during the study, the current cohort will be paused to 
allow review of the affected individuals by the DRSC before continuing dosing.  
AEs: 
 Four subjects experience a similar severe AE that is not clearly unrelated to the IMP, or 
 Two subjects experience a similar SAE that is not clearly unrelated to the IMP. 
Laboratory Abnormalities: 
Two subjects with an abnormality of both of the following parameters, whose temporal 
relationship to the IMP makes causality feasible, confirmed on repeat testing: 
 Serum ALT or AST >3 times the ULN or 2-fold above baseline if baseline is ≥ 1.5 times 
ULN. 
 Total serum bilirubin >2 times the ULN (>35% direct bilirubin). 
ECG Criteria: 
Three subjects fulfil the following ECG criteria based on the mean of triplicate measures (≥ 1 
minute apart), that will be completed once the first ECG demonstrates a prolonged interval: 
 QTcF ≥500 msec or uncorrected QT interval of >600 msec. 
6.5.2 
Suicidal Ideation and Behaviour 
Please refer to Section 8.8 for prospective assessment of suicidal ideation and behaviour. If a 
subject exhibits suicidal behaviour or active suicidal ideation with intent during the study, the 
Investigator should discontinue the subject and provide the appropriate treatment. 
6.6 
Subject Withdrawal from Study 
A subject will be considered withdrawn from study if the subject has permanently discontinued 
study drug or study procedures. The primary reason for withdrawal from study must be entered 


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into the eCRF. All subjects that permanently discontinue the study must make every effort to 
complete the Early Termination Visit. The discontinuation date will be the date of the Early 
Termination Visit, last date of study drug or study assessment whichever is later. 
For a subject who discontinues due to an AE, see Section 10.1.1 for follow-up procedures. 
Subjects can be withdrawn from the study for the following reasons: 
 Death 
 AE 
 Protocol non-compliance 
 Pregnancy (See Section 12) 
 Termination of the study 
 Upon the subject’s request (withdrawal of consent) 
 Significant deviation from the protocol 
 Concurrent illness or requirement for prohibited medication 
 At the discretion of the Investigator 
6.6.1 
Subject Withdrawal of Consent 
If a subject withdraws consent, the subject will not receive any additional doses of study drug 
(See Section 9 for a definition of “study drug”). However, the subject may be offered additional 
tests as needed to monitor their safety (e.g., EOS safety assessments or procedures). 
6.6.2 
Subjects Lost to Follow-up 
In cases of a missed visit, the Investigator or designee must attempt to contact the subject and re-
schedule as soon as possible. The Investigator or designee must counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether or not the subject 
wishes to and/or should continue in the study. 
In the event a subject is lost to follow-up, the Investigator or designee must make a reasonable 
effort to contact the subject. Two documented attempts (e. g., phone, email, etc.) to contact the 
subject followed by a certified mailed letter is considered reasonable. 
 


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7 
STUDY SUSPENSION OR TERMINATION 
Indivior reserves the right to temporarily suspend and/or permanently discontinue the study at 
any time and for any reason, including safety or ethical concerns or severe non-compliance. If 
such action is taken, Indivior will discuss the rationale for the decision with the PI. In cases 
where a study is suspended or terminated for safety reasons, Indivior will promptly inform 
Investigators and the Regulatory Authorities of this action and the reason(s) for the suspension or 
termination. 
If required by applicable regulations, the Investigator must inform the IRB promptly and provide 
the reason(s) for the suspension or termination. If the study is prematurely discontinued, all study 
data and drug substance remaining on-site will be returned to Indivior or its designated 
representative. 
 


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8 
DESCRIPTION OF STUDY PROCEDURES 
Study assessments and procedures, including the timing of assessments, are summarized in 
Schedule of Events tables for Part I, Part II and Part III (Section 22.1, Appendix 1, Section 22.2, 
Appendix 2 and Section 22.3, Appendix 3). Further details on PK and safety assessments are 
provided in Section 14.8 and Section 14.9, respectively. 
See Section 10 for description of AE procedures. 
8.1 
Informed Consent 
A signed written ICF (Informed Consent Form) must be obtained from the subject or a legal 
representative before any study assessments or procedures may be performed. The potential 
subject will be given the IRB-approved ICF to review and will have the opportunity to ask 
questions concerning the study until he or she is satisfied. The potential subject should be able to 
answer simple questions about the study after the ICF has been reviewed and explained. After 
this explanation, the potential subject will be asked to sign and date the written ICF. The PI or 
designee obtaining informed consent from the subject will also sign the ICF to confirm that 
consent has been obtained as required. A copy of the signed ICF will be given to the subject. 
8.2 
Demographics, Baseline Characteristics 
and Medical History 
The following demographic and baseline information will be captured: sex, race, age, ethnicity, 
height, weight and BMI. 
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 and any other noteworthy medical information. Any history of vasectomy 
in male participants should be recorded. Any updates to medical history information made 
available during the course of the study will be captured. 
 
 
8.3 
Physical Examination 
At Screening, a complete physical examination will include an assessment of general 
appearance, skin and extremities, head and neck, lymph nodes, eyes, ears, nose, throat, thyroid, 
neurological system, lungs, cardiovascular system, and abdomen (liver and spleen). The physical 
exam will include a testicular/epididymal examination but will not include a breast, pelvic or 
rectal examination unless clinically indicated.  


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After the screening period, brief physical examinations will occur consisting of heart, lung and 
abdomen and targeted for any AEs. For men, a testicular/epididymal examination will be 
performed at the End of Study visit. If any clinically significant change from screening is noted, 
it will be reported as an AE. 
Any clinically significant abnormalities, including changes from baseline, must be reported as 
AEs. Any findings from the testicular/epididymal examination, regardless of clinical 
significance, should be reported as an adverse event. 
8.4 
Vital Signs 
Blood pressure, heart rate, respiratory rate and temperature will be measured by automated 
recorders after the subject has been in a semi-recumbent position for a minimum of 3 minutes 
according to the time schedule presented in the Schedule of Events tables (Section 22.1, 
Appendix 1, Section 22.2, Appendix 2 and Section 22.3, Appendix 3). Blood pressure will be 
measured 3 times (at least 1 minute apart) pre-dose and the mean of the triplicate measures of 
blood pressure will define baseline SBP and DBP at the pre-dose timepoint. 
If a subject shows an abnormal assessment at any stage, a triplicate blood pressure measure will 
be taken at that timepoint, and the mean of the triplicate measures will be used for any subject 
discontinuation decisions. The abnormality will be followed to resolution if required. Additional 
measurements may be taken as deemed necessary by the Investigator (See Section 6.5.1.1). 
Any clinically significant abnormalities, including changes from baseline, must be reported as 
AEs. 
Pending emerging data, any changes in the timing or addition of time points for any planned 
study assessments must be documented and approved by the relevant study team member and 
then archived in the Sponsor and site study files, but will not constitute a protocol amendment. 
The IRB will be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF.  
8.5 
12-Lead Electrocardiograms 
A 12-lead ECG will be recorded after the subject has been in the semi-recumbent position for a 
minimum of 5 minutes as presented in the Schedule of Events tables (Section 22.1. Appendix 1, 
Section 22.2, Appendix 2 and Section 22.3, Appendix 3). 
A triplicate ECG will be recorded for the determination of the baseline result at pre-dose on Day 
1. For each numeric ECG parameter, the baseline value will be the mean of the 3 recordings. 
If a potentially clinically significant abnormality is noted during other ECG assessments, a 
triplicate ECG will be taken at that timepoint, and the mean of the triplicate measures will be 
used for any subject discontinuation decisions. All triplicate ECG recordings should occur at 
least 1 minute apart. If a subject shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution, if required. Additional 
measurements may be taken as deemed necessary by the Investigator (See Section 6.5.1.1). 


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Any clinically significant abnormalities, including changes from baseline, will be reported as 
AEs. 
8.6 
26-Hour Holter Monitoring 
8.7 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed at the time points listed in Section 22.1, Section 22.2 
and Section 22.3 in a licensed clinical laboratory. A serum pregnancy test will be conducted at 
screening, while all remaining pregnancy tests will be urine pregnancy tests performed using a 
licensed test (dipstick). Subjects are to be in a seated or semi-recumbent position during blood 
collection. 
The following clinical laboratory tests (Table 1) will be performed according to the Schedule of 
Events tables in Section 22.1, Appendix 1, Section 22.2, Appendix 2 and Section 22.3, Appendix 
3. 
Additionally, for Part III, fentanyl and oxycodone will be part of the UDS. 


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Table 1 List of Laboratory Tests 
Haematology 
Haematocrit 
Haemoglobin 
Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with differential (absolute count) 
 
Urinalysis: 
Appearance 
Bilirubin 
Colour 
Glucose 
Ketones 
Leucocyte esterase 
Microscopic examination of sedimenta 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Pregnancy: 
Serum hCG 
Urine hCG 
 
Molecular 
PCR for COVID-19 
 
Screening Only: 
FSH (as needed in post-menopausal females only) 
Haemoglobin A1c 
Hepatitis B surface Antigen 
Hepatitis C Antibody 
HIV-1 and -2 antibodies 
Prothombin Time with INR 
PTT 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase 
Gamma-glutamyl transferase 
Glucose  
Lactate dehydrogenase 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
 
Urine Drug Screen (UDS): 
Opioids 
Cocaine 
Amphetamines 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 
Ethanol 
In addition to the above, for Part III: 
Fentanyl 
Oxycodone 
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; INR = 
international normalized ratio; and PTT = partial thromboplastin time. 
a 
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to White Blood Cell count, Red Blood Cell 
count, casts and crystals). 
8.7.1 
Sample Collection, Storage and Shipping 
Details for the collection, preparation, storage and shipment of centrally tested laboratory 
specimens will be outlined in the Laboratory Manual. 


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8.8 
Columbia-Suicide Severity Rating Scale 
For this drug with CNS activity, procedures follow recommendations of the FDA Guidance for 
Industry: Suicidal Ideation and Behaviour: Prospective Assessment of Occurrence in Clinical. 
Trials. (Accessed at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/guidance-industry-suicidal-ideation-and-behavior-prospective-assessment-
occurrence-clinical-trials on 05 May 2023) 
The C-SSRS will be administered per the Schedule of Events in Section 22.1, Appendix 1, 
Section 22.2, Appendix 2 and Section 22.3, Appendix 3. The C-SSRS is a questionnaire 
designed for assessment of suicidal ideation and behaviour in adolescents and adults (Posner 
2011). The questionnaire takes only a few minutes and must be administered by the PI or 
delegated to a suitably qualified individual by education and/or training. Clinical study versions 
of the questionnaire are available for study screening and follow-up visits. 
If a subject exhibits suicidal behaviour or active suicidal ideation with intent during the study, 
the Investigator should discontinue the subject and provide the appropriate treatment. 
8.9 
Pharmacokinetic Assessments 
8.9.1 
Plasma Samples for Pharmacokinetic Analysis 
8.9.2 
Sample Bioanalysis 


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8.10  Pharmacodynamic Outcomes 
Pharmacodynamic outcomes will be performed as presented in the Schedule of Events tables 
(Section 22.1. Appendix 1, Section 22.2, Appendix 2 and Section 22.3, Appendix 3). 
8.10.1 
Part I, Part II and Part III 
8.10.2 
Part III Only 


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8.11 Appropriateness of Measurements 
The clinical data measures to be employed in this study are standard, generally accepted 
measures used for decision-making in clinical practice. 
The conventional safety assessments that will be used in this study are suitable, standard and 
widely used measures for evaluating the safety of the study drug. Measurement of drug levels in 
plasma over time is standard for the evaluation of PK parameters. 
8.12 Protocol Deviations 
A protocol deviation is any non-compliance with the clinical study protocol or ICH/GCP 
requirements. The non-compliance may be either on the part of the subject, the Investigator or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly and in accordance with ICH E6 Good Clinical Practice guidelines. It 
is the responsibility of the Investigator and study site staff to use continuous vigilance to identify 
and report deviations to Indivior or specified designee and the IRB per the IRB’s reporting 
requirements. The Investigator and study site staff are responsible for knowing and adhering to 
the IRB’s requirements. Protocol deviations must be documented and will be included in the 
final study report. 
8.13 Order of Procedures 
Acceptable windows for assessment timepoints are located in the footnotes of the Schedule of 
Events tables, Section 22.1 Appendix 1, Section 22.2 Appendix 2 and Section 22.3, Appendix 3. 
It is recommended that on days/times with multiple assessments, the assessments are completed 
in the following order, when applicable. 
 
 safety ECG tracings 
 Vital signs 
 Blood collection for plasma PK assessments and clinical safety laboratories 
 PD assessments as applicable 


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9 
STUDY DRUG MANAGEMENT 
9.1 
Description 
The term “study drug” is used throughout the protocol to describe INDV-2000, placebo and/or 
the SUBOXONE SL film received by the subject as per the protocol design. The term “IMP” is 
used throughout the protocol to refer to INDV-2000 and its placebo. 
9.1.1 
Drug Manufacturer 
9.1.2 
Placebo 
9.1.3 
Blinding and Randomization 
Part I and II of this study will be double-blinded to include the healthy volunteers, the 
Investigator and site staff. The clinical pharmacist and his/her designated team members 
responsible for IMP dispensation will be unblinded. The DRSC members will be blinded except 
for the Indivior PK scientist. The DRSC will review blinded clinical safety and laboratory data. 
Blinded PK data for dose escalation decisions may be presented, and if PK data cannot be 
presented in a blinded manner, the unblinded PK scientist will make blinded statements 
regarding those data to aid in dose escalation decisions. The Sponsor team may unblind after the 
dose escalation decision per cohort has been made (Section 15.2).  


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The randomization schedule and disclosure envelopes will be generated by an unblinded 
statistician. The unblinded statistician will not be involved in any decisions relating to the study 
prior to unblinding. Prior to database lock and unblinding, all randomization materials, including 
the final signed and dated randomization schedule, will be held by the Indivior unblinded 
statistician. 
A copy of the randomization schedule will also be made available to the unblinded team at the 
clinical site, as well as the laboratory performing the bioanalysis to allow selective analysis of 
PK samples to measure drug concentrations. 
Interim PK parameter calculations will be performed using bioanalytical data with dummy 
subject numbers and initials in order to maintain the study blind. Interim PK analyses will be 
performed using nominal time points. 
One set of disclosure envelopes (i.e., sealed envelopes containing individual subject 
randomization details) will be provided. This set will be held in a secure and locked cabinet in a 
temporary drug room, having key fob-controlled access, located just outside the pharmacy. 
Disclosure envelopes may be used by the Investigator in the event of an emergency, or if the 
Investigator deems it necessary to break the study blind in the interest of a subject’s medical 
safety, or if warranted during scheduled safety reviews. Any request for information on the 
randomization schedule after initial issue must be made using a randomization disclosure form, 
except in the case of emergency unblinding. The date, time and reason for the unblinding must 
be captured in the source documentation. The Indivior Medical Monitor must be contacted as 
soon as possible when an unblinding has occurred, and not later than 24 hr following disclosure 
of IMP assignment. 
Details of any disclosure of the randomization schedule will be documented and retained in the 
investigator site file (ISF). 
If any blinded study team member suspects that they have been unblinded, they are to 
immediately notify the Indivior unblinded contact. The suspected unblinded information must 
not be forwarded or revealed to any other blinded team members. 
Subjects who are unblinded due to an adverse event will be discontinued from the study and 
asked to complete an Early Termination Visit. In any instance of accidental subject unblinding, 
the Indivior Medical Monitor must be alerted as soon as possible and no later than 24 hours after 
awareness. The decision to continue/discontinue the subject will be made after consultation with 
the Indivior Medical Monitor. 
The study blind will be broken after the completion of Part II of the study and the data have been 
locked. 


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9.1.4 
Parts I and II 
For Part I and Part II, there are 4 planned cohorts. 
Part I, Cohort 1 (QD Dosing) 
For in-clinic dosing, healthy volunteers will receive INDV-2000 following a fast of at least 2 
hours. Healthy volunteers will be administered INDV-2000 with 240 mL (8 ounces) of water. No 
food will be allowed for at least 1-hour post-dose administration. Water is allowed as desired 
except for at least 1 hour before and at least 1 hour after drug administration.  
Part I, Cohort 2 and Part II, Cohorts 1 and 2 (BID Dosing) 
For in-clinic dosing, healthy volunteers will receive their first dose of INDV-2000 in the 
morning following a fast of at least 2 hours. Healthy volunteers will receive their second dose of 
INDV-2000 12 hours later, following a fast of a least 2 hours. Healthy volunteers will be 
administered INDV-2000 with 240 mL (8 ounces) of water. No food will be allowed for at least 
1-hour post-dose each administration. Water is allowed as desired except for at least 1 hour 
before and at least 1 hour after each drug administration. For outpatient dosing, healthy 
volunteers will be instructed to administer their first dose of INDV-2000 in the morning 
following a fast of at least 2 hours, and their second dose 10-12 hours later, also following a fast 
of a least 2 hours. Healthy volunteers will be instructed to wait at least 1 hour before eating after 
each dose. On outpatient visit days, healthy volunteers will be instructed to not dose their 
morning dose prior to their clinic appointment and wait to dose until instructed by site staff. 
See Table 2 for summary of projected dose per cohort. 


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Table 2 Part I and Part II Multiple Ascending Study Drug Dosing: Projected Doses 
Cohort 
 
Part I, 
Cohort 1 
Part I, 
Cohort 2 
Part II, 
Cohort 1 
Part II, 
Cohort 2 
Dose 
 
Active 
N=9 
INDV-2000 
100 mg QD 
INDV-2000 
100mg BID 
INDV-2000 
200mg BID 
INDV-2000 
400mg BID  
Placebo 
N=3 
INDV-2000 
Placebo 
INDV-2000 
Placebo 
INDV-2000 
Placebo 
INDV-2000 
Placebo 
Safety and PK evaluation at each dose level. 
9.2 
Packaging, Labelling and Storage 
9.2.1 
Packaging and Labelling 
9.2.2 
Storage Conditions 
9.2.3 
Drug Shipment 
9.3 
Drug Administration 
The study drug must be dispensed under the supervision of the Investigator or a suitably 
qualified member of the study team. The Investigator or designee agrees to store and dispense 
the study drug per this protocol. 


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9.3.1 
Part III 
Part III dosing of INDV-2000 will be open-label at projected doses determined after review of 
Part II, Cohort 2 data, and will not exceed the highest total daily dose leveraged in Part II, Cohort 
2 of the study.
 
 
Subjects will receive their first dose of INDV-2000 in the morning following a fast of at least 2 
hours. For twice daily dosing, subjects will receive their second dose 12 hours later, also 
following a fast of a least 2 hours. No food will be allowed for at least 1 hour after each dose 
administration. Water is allowed as desired except for at least 1 hour before and at least 1 hour 
after each drug administration. 
 
9.4 
Accountability 
The Investigator is responsible for ensuring that all study drug is inventoried, accounted for and 
documented in accurate accountability records. Upon completion of the study and/or as 
requested by Indivior, copies of study drug and drug substance accountability records will be 
provided to Indivior. After the monitor completes reconciliation and after Indivior has approved 
the commencement of destruction, all unused study drug will be destroyed by the Investigator, as 
per local standard operating procedures (SOP). The IMP must be handled strictly in accordance 
with the protocol, handling guidelines and the label. 
Subject level dispensation of study drug must be documented on the appropriate subject level 
accountability form. All study drug dispensation will be performed by a pharmacist or designee, 
checked by a study site staff member and documented on a drug dispensation form. 
Used study drug bottles (for both INDV-2000 and placebo), used SUBOXONE SL film pouches, 
and unused study drug must be available for verification by the site monitor during monitoring 
visits. 
9.5 
Reporting Product Complaints 
The Investigator and study site staff are responsible for prompt reporting of product quality 
complaints to Indivior. A product complaint is any concern pertaining to the preparation or 
quality of the study drug, and includes, but is not limited to, 
, labelling defects or 
packaging defects, study drug that is thought to be ineffective, or has an appearance, taste or 
odour that is outside of what is expected. 
All product complaints must be reported to Indivior 
 in a timely 
manner and the following information provided: 
 study number 
 site contact/reported by 
 subject number (if already assigned to a subject) 
 description of issue 


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 picture, if available (photographs are to be taken only if safe to do so/within site policy or 
practice to take photograph) 
Retain the product and packaging in quarantine for further investigation, as required. 
9.6 
Prior and Concomitant Therapies 
Therapies and medications will be collected from screening until the EOS visit or the ET visit, at 
the time points listed Section 22.1, Appendix 1, Section 22.2, Appendix 2 and Section 22.3, 
Appendix 3. Any concomitant medications (including herbal preparations) taken during the study 
will be recorded in the source documents and in the eCRF. Any changes in concomitant therapy 
and medications during the study will be documented, including cessation of therapy and 
medication, initiation of therapy and medication and dose changes. 
Prior therapies and medications are considered any medication ended prior to first dose of study 
drug. Therapies and medications are considered concomitant if taken after dosing with IMP. 
For Part III, therapies and medications taken after study drug but prior to IMP are considered 
run-in therapies and medications. 
Any changes to concomitant therapies and medications that are not listed as permitted 
concomitant therapies and medications must be discussed with the study Medical Monitor. 
9.6.1 
Permitted Concomitant Therapies 
The Investigator may prescribe concomitant medications or treatments for pain (acetaminophen 
up to 2000 mg per 24 hr, ibuprofen up to 600 mg per 24 hr administered orally) or nausea 
(promethazine 25 mg oral or suppository) as deemed necessary for the comfort of the subject. 
For oral therapies, dosing must be withheld for at least 2 hr before or 1 hr after administration of 
IMP. Additionally, in Part III of the study, non-opioid rescue medications to treat drug 
withdrawal signs and symptoms will be allowed in the study based on the Investigator’s medical 
judgment. In Part III, if a subject screen fails, discontinues or completes the study, they will be 
given options for their continued treatment for OUD by the clinical facility. 
9.6.2 
Prohibited Concomitant Therapies 
Subjects will be instructed not to take any medications, including over-the-counter products, 
without first discussing with the Investigator. 
The following medications are CYP3A4 inhibitors or inducers and are expressly prohibited 
during study participation: 
Strong inhibitors of CYP3A4 include clarithromycin, telithromycin, nefazodone, itraconazole, 
ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, 
tipranavir. Moderate inhibitors of CYP3A4 include amiodarone, erythromycin, fluconazole, 


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miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan. 
Cimetidine is an over-the-counter medication that is a weak CYP3A4 inhibitor. 
Strong and moderate inducers of CYP3A4 include carbamazepine, phenytoin, rifampin, St 
John’s wort, bosentan and phenobarbital. 
Indivior or specified designee must be notified as soon as the site is aware that the subject 
received any of these medications during study participation to determine if they are to be 
discontinued. 
9.6.3 
Lifestyle Restrictions 
9.6.3.1 
Fluid and Food Intake (Parts I, II and III) 
Dosages 
 should be swallowed whole. Healthy volunteers/subjects must 
avoid poppy seeds, grapefruit and grapefruit juice while on study drug.  
Restrictions for water and food intake related to study drug administration are discussed in 
Section 9.3. 
9.6.3.2 
Subject Activity Restrictions (Parts I, II and III) 
Subjects will not be permitted to perform heavy exercise while housed in the clinical unit. For 
the outpatient portion of the study, subjects will be asked to refrain from heavy exercise that 
could result in muscle soreness starting 24 hours before IMP administration and before 
outpatient safety visits. 
9.6.3.3 
Caffeine, Alcohol and Tobacco Restrictions (Parts I and II, but Not Part III) 
From 90 days prior to screening, subjects will refrain from smoking and from using e-cigarettes 
and nicotine-containing products through the EOS visit. 
From 24 hours prior to the Day -1 check-in, through discharge from the in-clinic period, subjects 
will not be permitted to drink caffeine-containing beverages, eat caffeine-containing foods or use 
caffeine-containing products. 
From 24 hours prior to the Day -1 check-in, through discharge from the in-clinic period, subjects 
will not be permitted to drink alcohol. Subjects must refrain from heavy alcohol use (>2 
drinks/day for women and >3 drinks/day for men) from discharge through the EOS visit. 
9.7 
Compliance 
The PI or sub-Investigator may terminate a subject based on the subject’s inability to comply 
with the protocol requirements. 


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In Part I and Part II, study drug will be dispensed by an unblinded member of the site staff, and it 
will be administered by designated qualified blinded study personnel at the clinical facility. Part 
III is open label and, as such, all parties are unblinded. The PI or sub-Investigator will be present 
during the in-clinic administration of study drug. The time and duration, the dose delivered and 
any in-clinic dosing observations will be recorded in source documentation. Study drug 
administration conducted by the subject on outpatient dosing days will be recorded in the 
subject’s dosing diary. The PI, sub-Investigator or designated individual will maintain a log of all 
study drugs dispensed and returned. Drug supplies will be inventoried and accounted for 
throughout the study. The clinical site will have access to the Indivior Medical Monitor for any 
safety events that occur. 
10 ADVERSE EVENTS 
The Investigator or designee is responsible for identifying, documenting and reporting events 
that meet the definition of an AE. 
An AE is any untoward medical occurrence in a subject associated with the use of a study drug 
regardless of the presence of a causal relationship to the study drug. An AE can be any 
unfavourable and unintended sign (including an abnormal laboratory finding) symptom or 
disease (new or exacerbated) temporally associated with a study drug, whether or not considered 
related to the study drug. 
Events meeting the definition of an AE include: 
 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 of either study drug or a 
concomitant medication. 
 Symptoms and/or the clinical sequelae of an overdose of study drug. Overdose per se will not 
be reported as an AE/SAE. 
 Signs, symptoms or the clinical sequelae resulting from special interest conditions (e.g., 
study drug misuse, medication error, study drug withdrawal, etc.). 
 Symptoms and/or clinical sequelae that resulted in intervention. 
Events that do not meet the definition of an AE include: 
 Medical or surgical procedures; the condition that leads to the procedure is an AE. 
 Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital, 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 study drug will be 
reported as described in this protocol. 
Adverse events should be volunteered by the subject or solicited from the subject using a 
standard statement, obtained from examination of the subject at a 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 study drug-related or not. 
10.1.1 
Time Period for Collecting Adverse Events 
Adverse event monitoring and reporting will begin after subjects sign the ICF, continue 
throughout the study and include EOS/ET/Follow-up. Subjects will be monitored by the study 
site staff for untoward effects and will be released from the study after the last procedure is 
completed and confirmed that the subject has no residual untoward effects from the study drug 
that may affect safety. Treatment-emergent AEs will be defined as events observed after starting 
administration of INDV-2000 or placebo. For Part III, run-in AEs will be defined as events 
observed after starting SUBOXONE SL film and before starting INDV-2000. 
Surgical procedures, planned before enrolment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion. In this case the medical condition is to 
be reported in the subject’s medical history. 
Any clinically significant symptoms will be reported as AEs. All AEs and corresponding 
treatment will be recorded in the eCRFs and a summary of all safety data will be presented in the 
final Clinical Study Report (CSR). Any ongoing AEs will be appropriately followed up until 
resolution or 14 days after EOS/ET. If findings are noted in the 90 day post last dosing day 
safety follow up call for male participants, these will be recorded as Adverse Events and 
followed until completion of required assessments. The study site personnel will make every 
effort to contact the subject as outlined in Section 6.6.2,  after which the outcome of the AE will 
be considered ongoing and the subject will be noted in source as lost to follow-up. 
If a subject experiences the onset of an SAE within 5 days following study completion and in the 
opinion of the Investigator, that SAE is associated with the study drug, it will be followed and 
reported as described in Section 11.2. 


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If an SAE occurs that is deemed related to study drug, a PK sample will be taken as soon as 
possible after the event is reported. If possible, an additional sample should be collected when 
the SAE has been resolved. 
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. 
 
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. 
An event existing prior to study drug administration and worsening in intensity post-study drug 
administration will be recorded as a new event. For events that occur after the first study drug 
administration, the maximum intensity, toxicity (Parts I and II only), and seriousness should be 
reflected in the event record. 
Parts I and II only: For any applicable events appearing in the Toxicity Grading Scale 
considered by the Investigator to be an adverse event according to Section 10.1.4, the intensity of 
adverse events will be graded in accordance with the FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (Section 22.6, Appendix 6). Any event not falling under one of the specific 
categories listed will be graded as above.  
 
10.1.3 
Assessment of Causality 
The Investigator or a medically qualified sub-Investigator, trained on this study protocol and 
listed on the delegation of authority log is responsible for determining the AE relationship to the 
study drug. 
The following categories will be used to define the relationship of an AE to the administration of 
the study drug: 
 Not Related: 
Data are available to identify a clear alternative cause for the AE other 
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 Related: 
The cause of the AE is related to the study drug and cannot be 
reasonably explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy and/or other interventions). 
A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. The Investigator will 
use clinical judgment to determine the relationship. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors and the temporal relationship of 
the event to the study drug will be considered and investigated. The Investigator will also consult 
the IB 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 to Indivior or designated representative. However, it is 
imperative that the Investigator always make an assessment of causality for every event prior to 
the initial transmission of the SAE 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 
treatment, and/or requires temporal or permanent discontinuation of study drug, or a change to 
dosing other than as permitted by protocol, or if considered to be clinically significant by 
Investigator or medically qualified designee. 
Screening laboratory assessments, if determined to be clinically significant by the Investigator, 
are not AEs.  
 


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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 
 In-patient hospitalization or prolongation of existing hospitalization 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect in the offspring of a subject who received INDV-2000 
 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 in-patient hospitalization 
o Development of study drug abuse or diversion 
 Potential Hy’s Law cases indicative of medication-induced hepatocellular injury, defined as: 
o ALT ≥3x ULN and total bilirubin of ≥2x ULN (or INR >1. 5 if measured) 
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 Section 22.4, Appendix 4. 
An AE is considered “life threatening” if the subject was at immediate risk of death from the 
event as it occurred; i.e., it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, study drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening even though study drug-
induced hepatitis can be fatal. 
AEs requiring hospitalization will be considered SAEs. Hospitalizations for elective surgery or 
routine clinical procedures that are not the result of an 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. 


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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 the SAE on the appropriate 
electronic or paper form(s). 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to 
Indivior in lieu of completion of the SAE Reporting Form. However, there may be cases where 
copies of medical records are requested by Indivior or designated representative. In this instance, 
all subject identifiers, with the exception of subject number, will be redacted on the copies of the 
medical records prior to submission to Indivior. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms 
and/or other clinical information. In such cases, the diagnosis will be documented as an AE or 
SAE and not the individual signs/symptoms. 
Additional PK samples may be collected for subjects who experience an SAE. Samples should 
be collected as soon as the Investigator is made aware of the SAE and additional blood samples 
may be collected after resolution of the SAE. 
11.2 Reporting Serious Adverse Events 
11.2.1 
Investigator Reporting of Serious Adverse Events 
Once the Investigator determines that an event meets the protocol definition of an SAE, the SAE 
will be reported to Indivior (or designated representative) by the Investigator (or designee) 
within 24 hours from first being aware of the event using the form provided by Indivior or 
designated representative. Any follow-up information on a previously reported SAE will also be 
reported to Indivior within 24 hours. 
Where additional information is needed or expected, the Investigator will not wait to receive all 
information before reporting the event to Indivior. The Investigator must provide an assessment 
of causality at the time of the initial report as described in Section 10.1.3. 
In the event of an SAE, the Investigator or designee will notify both the Indivior Medical 
Monitor at the phone number and/or email address listed under Study Personnel Information and 
Indivior Pharmacovigilance by completing the appropriate form(s). A paper SAE Reporting 
Form must be completed and submitted to Indivior Pharmacovigilance: 


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11.2.2 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt receipt of notifications of SAEs to Indivior or designated representative from 
Investigators is essential in ensuring that legal obligations and ethical responsibilities regarding 
the safety of subjects are met. 
Indivior has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the IMP. Indivior or designated representative will 
comply with country-specific regulatory requirements pertaining to safety reporting to 
Regulatory Authorities, IRBs and Investigators. 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE related to the IMP 
administered in any dose and that, in its nature or severity, is inconsistent with the IB. Indivior 
Pharmacovigilance will determine if an SAE meets the definition of a SUSAR and distribute 
SUSAR reports according to local regulatory requirements and Indivior policy. An Investigator 
who receives an Investigator safety report describing an SAE or other specific safety information 
(e g., summary or line listing of SAEs, Dear Investigator Letter) will file it with the IB and will 
notify the IRB, if required according to local requirements. 
11.2.3 
Overdose 
Any instance of overdose with concomitant medications or illicit drugs must be communicated 
as an SAE and fully documented. Any symptoms of overdose with study drug would be assessed 
according to criteria for treatment-emergent and SAEs outlined in sections above. Details of any 
signs or symptoms and their management should be recorded, including details of any antidote(s) 
administered. 
 
 


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12 PREGNANCY 
In the case where a subject’s routine pregnancy test as required per protocol is positive for 
pregnancy prior to dosing, the subject must not be dosed. If the subject has a positive urine 
pregnancy test, a confirmatory serum pregnancy test will be performed. 
12.1 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 90 days of the last exposure to study drug, treatment will be 
immediately stopped, where applicable. The subject will be instructed to return to the clinical 
unit as soon as possible (preferably within 48 hours) to undergo a serum pregnancy test. If the 
result of the serum pregnancy test confirms the subject is pregnant, the subject will be 
discontinued from the study and will undergo all final study visit procedures (with the exception 
of any additional pregnancy testing). 
In the case where a subject’s routine pregnancy test as required per protocol is positive for 
pregnancy, treatment will be immediately stopped. If the subject has a positive urine pregnancy 
test, a confirmatory serum pregnancy test should be performed. The subject will be discontinued 
from the study and complete final study visit procedures (with the exception of any additional 
pregnancy testing). The Investigator should fully inform the female subject of the serious risk to 
the foetus as well as discuss the desirability of continuing the pregnancy. 
The Investigator will record pregnancy information on the appropriate form and submit it to 
Indivior or designated representative within 24 hours of learning of the pregnancy. The subject 
will also be followed to determine the outcome of the pregnancy and information on the status of 
the mother and child will be forwarded to Indivior or designated representative. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
premature termination of the pregnancy will be reported regardless of foetal status (presence or 
absence of anomalies) or indication for procedure. 
12.2 Action to be Taken if Pregnancy Occurs 
in a Female Partner 
If the partner of a study subject becomes pregnant within 90 days of the last dose of study drug, 
the pregnancy will be reported to the clinical unit within 48 hours of the subject’s knowledge of 
the pregnancy. The Investigator will attempt to collect pregnancy information on any female 
partner of a randomized male study subject who becomes pregnant while participating in this 
study. 
After obtaining the necessary signed informed consent from the female partner directly, the 
Investigator will record pregnancy information on the appropriate form and submit it to Indivior 
or designated representative within 24 hours of learning of the partner’s pregnancy. The partner 
will also be followed to determine the outcome of the pregnancy and information on the status of 


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the mother and child will be forwarded to Indivior or designated representative. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
premature termination of the pregnancy will be reported regardless of foetal status (presence or 
absence of anomalies) or indication for procedure. 


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13 DATA MANAGEMENT 
13.1 Data Collection and Management 
Data will be entered into subject eCRFs in a validated, access-controlled Clinical Data 
Management System (CDMS) and will be combined with other data captured centrally outside of 
the eCRF in a secure computing environment. Clinical data will be collected and managed in 
accordance with a study-specific data management plan to ensure that integrity of the data is 
maintained. Adverse events and medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Prior and concomitant medications will be coded using the 
World Health Organization (WHO) Drug Dictionary. Completed eCRFs (including data queries 
and audit trail) will be retained by Indivior. Electronic copies of completed eCRFs will be sent to 
the Investigator for their records. Subject identifiers will not be collected or transmitted to 
Indivior, according to Indivior standards and procedures. 
13.1.1 
Database Quality Assurance 
Subject 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 programmatically and/or manually and addressed by the 
investigational site. Only authorized personnel will make corrections to the eCRFs, and all 
corrections will be documented in the CDMS audit trail. 
13.1.2 
Source Documents 
The Investigator is responsible for the quality of the data recorded in the eCRFs. The data 
recorded must be a complete and accurate account of the subject’s record collected during the 
study. 
Study data are not to be gathered directly onto the eCRF but must be gathered onto primary 
source documents at the clinical site. Completion of source documents will precede the 
completion of the eCRF. Source documents may be electronic, hard copy, or a combination of 
both 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 eCRF will be considered 
the source document for individual eCRF elements such as study-specific scales if those data are 
collected directly onto an eCRF. 
 


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14 STATISTICS 
14.1 General Procedures 
This section describes the sample size, analysis populations and planned analyses for primary, 
secondary and exploratory endpoints and for safety assessments. A comprehensive statistical 
analysis plan (SAP) will be developed to detail the statistical methodology for all aspects of the 
planned analyses. The SAP will be approved after the protocol is finalized and before the 
database is locked. Any deviations from the analyses described below will be identified in the 
SAP (and subsequently the CSR). Any unplanned analyses not described in the SAP will be 
identified in the CSR. 
Data will be listed and summarized separately for Parts I, II and III of the study. For Parts I and 
II, data will be summarized by dosing cohort for active treatment and for placebo subjects 
combined over all dosing cohorts. 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 and the percentage of subjects in 
corresponding categories. Individual subject data will be presented in data listings. Data listings 
will include all data collected from enrolled subjects. 
For change from baseline calculations, baseline will be defined as the last measurement taken 
prior to administration of IMP (INDV-2000 or placebo for Parts I and II, and INDV-2000 for 
Part III). For blood pressure and numeric ECG parameters, triplicate means will be used for 
baseline. 
14.2 Sample Size 
Part I (2 cohorts) and Part II (2 cohorts): Each cohort will be composed of 12 healthy volunteers 
(9 receiving active and 3 placebo). A total of 48 healthy male and female volunteers are planned 
to participate in both parts. Study subjects who are randomized but do not receive study drug will 
be replaced. 
Part III: A single group of up to 16 treatment seeking subjects with OUD are planned to 
participate. 
The sample sizes are not based on formal power calculations because the study is designed to 
provide preliminary descriptive assessments of the safety, tolerability and PK for INDV-2000. 
The sample sizes used are typical for studies of this nature and should be adequate to assess the 
parameters described. 
14.3 Analysis Populations 
14.3.1 
Safety Population 
The Safety Population is defined as subjects who received at least one dose of IMP. 


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14.3.2 
Run-In Safety Population 
The Run-In Safety Population is defined as subjects who received at least one dose of study drug 
during the Part III run-in period. 
14.3.3 
Pharmacokinetic Population 
The PK analysis population is defined as subjects who received at least one dose of INDV-2000,  
have an adequate number of PK samples collected to derive any PK parameter, and have no 
protocol deviations that would significantly alter plasma concentration of INDV-2000. 
14.4 Demographic and Baseline 
Characteristics 
Demographic and baseline characteristics (e.g., sex, race, age, weight, height, BMI) will be 
summarized for the Safety and PK Populations, and separately for screen failures and run-in 
failures. 
14.5 Extent of Exposure 
Exposure will be summarized for the Safety Population. Exposure parameters will include total 
number of doses, dose duration, percentage of expected number of doses, and a binary variable 
for number of doses < 80% of expected. For Part II, percentage of expected doses and the binary 
variable will be summarized both overall and separately for in-patient vs. outpatient dosing. For 
Part III, exposure will be summarized for both INDV-2000 and buprenorphine. 
14.6 Prior and Concomitant Medications 
Prior and concomitant medications will be summarized by WHO Drug Dictionary medication 
class and standardized name. 
14.7 Study Endpoints 
14.7.1 
Primary Endpoints 
The primary endpoints for Parts I, II and III are the incidence, severity and relatedness of 
TEAEs; treatment-emergent SAEs (TESAEs); TEAEs leading to discontinuation; and fatal 
TEAEs. The primary endpoints will be assessed from first IMP dose through the final follow-up 
and will be summarized for the Safety Population as descriptive statistics only. 
14.7.2 
Secondary Endpoints 
Secondary endpoints for Parts I and II will be PK parameters of INDV-2000 following dosing on 
Days 1 and 7, and Day 28 (Part II). PK parameters will be summarized as descriptive statistics 
for the PK Population and will comprise Cmax, Tmax and AUC0-24 or 0-12 for INDV-2000. 


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There are no secondary endpoints for Part III. 
14.7.3 
Exploratory Endpoints 


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14.8 Pharmacokinetic Analysis 


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14.9 Safety Assessments 
Safety parameters will be summarized for the Safety Population and will comprise TEAEs, 
laboratory evaluations, vital signs, 12-lead ECG findings, physical examination findings and C-
SSRS assessments. 
14.9.1 
Treatment-Emergent Adverse Events (TEAEs) 
A TEAE is defined as an AE with start date/time at or after dosing with IMP. The number and 
percentage of subjects reporting TEAEs will be presented for each treatment by MedDRA 
system organ class (SOC) and preferred term (PT), each in descending order of frequency among 
all subjects in the given part of the study (then alphabetically in case of ties). 
Incidence and number of study drug-related TEAEs, TESAEs, study drug-related TESAEs, 
TEAEs leading to death, TEAEs leading to IMP discontinuation, and TEAEs leading to IMP 
interruption will be presented both in an overall summary table and by SOC and PT. Included in 
the overall summary table will be incidence and number of severe TEAEs and TEAEs with grade 
3 or higher toxicity grade (applicable for Parts I and II only). TEAE incidence will also be 
summarized by maximum severity within SOC and PT. Incidence of TEAEs will be summarized 
by PT only (not SOC) in descending order of incidence among all subjects (within study part). 
In summaries by severity and relationship to study drug, if more than one TEAE is coded to the 
same PT for the same subject, the subject will be counted only once for that PT using the most 
severe/most related occurrence. Missing severity, toxicity, and relatedness will be queried until 
resolution. 
Non-TEAEs and, for Part III, run-in AEs in the Run-In Safety Population will be summarized 
separately. 
Separate listings will be presented for TEAEs, TESAEs, TEAEs leading to IMP interruption or 
discontinuation and TEAEs leading to death. 
 
14.9.2 
Laboratory Evaluations 
Laboratory evaluations will be summarized as observed values and changes from baseline by 
analysis visit. Normal/abnormal shifts from baseline will also be summarized. 
14.9.3 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be summarized as 
observed values and changes from baseline by analysis visit. For SBP and DBP, baseline will be 
defined as the mean of triplicate measurements. 


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14.9.4 
12-Lead Electrocardiogram 
Numeric 12-lead ECG parameters will be summarized as observed values and changes from 
baseline by analysis visit, with baseline defined as the mean of triplicate measurements. ECG 
interpretation will be summarized by visit as a categorical variable, with baseline interpretation 
defined as the majority of the triplicate assessments; if there is no majority, the Sponsor will be 
notified and will provide a baseline interpretation based on a review of the data. 
14.9.5 
Physical Examination 
Clinically significant physical examination changes from screening will be reported as AEs; 
therefore, there will be no separate listings or summaries of physical examination findings. 
14.9.6 
Columbia-Suicide Severity Rating Scale 
The composite endpoints Suicidal Ideation and Suicidal Behaviour will be derived from the 
following 10 binary C-SSRS questions, reordered from the actual scale to facilitate the 
derivation: 
 
Question 1 
Wish to be Dead
Question 2 
Non-specific Active Suicidal Thoughts
Question 3 
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Question 4
Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Question 5
Active Suicidal Ideation with Specific Plan and Intent
Question 6
Preparatory Acts or Behaviour
Question 7 
Aborted Attempt
Question 8
Interrupted Attempt
Question 9
Actual Attempt (non-fatal)
Question 10
Completed Suicide
Suicidal Ideation is derived as “yes” if any of Question 1-5 has a “yes” response. Suicidal 
Behaviour is derived as “yes” if any of Question 6-10 has a “yes” response. If there are zero 
“yes” responses and at least one question has a missing response, the derived composite will be 
missing. Suicidal Ideation and Suicidal Behaviour will be summarized as a categorical variable 
by analysis visit. 
14.10 Pharmacodynamic Outcomes 


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14.11 Interim Analysis 
For Parts I and II there will be a blinded review of the safety and applicable PK data after 
completion of each cohort, before dose escalation. The safety data review will be conducted by 
the DRSC (Section 15.2) using stopping rules defined in Section 6.5. 
14.12 Handling of Missing Data 
In general, missing data (caused by premature discontinuation or otherwise) will not be imputed. 
15 ETHICS AND RESPONSIBILITIES 
15.1 Good Clinical Practice 
Prior to site activation, Indivior or a designated representative will obtain approval/favourable 
opinion from the relevant regulatory agency(ies) to conduct the study in accordance with 
ICH/GCP and any applicable country-specific regulatory requirements. 
The study will be carried out in accordance with the protocol and with local legal and regulatory 
requirements, ICH/GCP and all applicable subject privacy requirements. 
15.2 Data Review and Safety Committee 
The DRSC will include the Investigator, Sponsor Medical Monitor and PK scientist. Other 
members will be added as necessary. The DRSC members will be blinded except for the PK 
scientist. The DRSC will review blinded clinical safety and laboratory data. Blinded PK data for 
dose escalation decisions may be presented, and if PK data cannot be presented in a blinded 
manner, the unblinded PK scientist will make blinded statements regarding that data to aid in 
dose escalation decisions. Individual participant data may also be reviewed as needed (See 
Section 6.5). Based on the data presented, the DRSC may choose to unblind the data to the 
Sponsor only prior to making a dose escalation decision. Every effort will be maintained to keep 
the Investigator blinded. The proposed dose escalation scheme for Part I and Part II is described 
in the study design section; however, a more conservative dose escalation may be explored based 
on PK, safety and/or clinical observations. Dose escalation factors will be dependent upon 
observed safety, tolerability and PK. 
 
 
  
15.3 Institutional Review Board 
The protocol, ICF(s) and any other written information and/or materials to be provided to 
subjects will be reviewed by an independent and appropriately constituted IRB. If required by 
local regulations, the protocol should be re-approved by the IRB annually. The IRB must be 
constituted and operate in accordance with the principles and requirements of ICH/GCP. 


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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 or 
designated representative. 
15.4 Informed Consent 
The Investigator or a person designated by the Investigator (if allowed by local regulations) is to 
obtain written informed consent from each subject prior to entering the study. All written 
informed consent documents are required to have been reviewed and received a favourable 
opinion/approval from an IRB prior to presenting them to a potential subject. 
Any changes to the ICF must be reviewed by Indivior before submission to the IRB. 
The written informed consent process will include the review of oral and written information 
regarding the purpose, methods, anticipated duration and risks involved in study participation. 
The Investigator is to ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided. The Investigator or a person designated by 
the Investigator must also explain to each subject that participation is voluntary, and that consent 
can be withdrawn at any time and without reason. Subjects will receive a signed and dated copy 
of the signed ICF before any study-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. 
15.5 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, Indivior or regulatory inspection) along with the facility, study personnel and supporting 
systems/hardware. All documents pertaining to the study, including all versions of the approved 
study protocol, copy of the ICF and other documents as required per local laws and regulations 
(e. g., Health Insurance Portability and Accountability Act [HIPAA] documents), completed 
CRFs, source records (subject records, subject diaries, hospital records, laboratory records, drug 
accountability records, etc. ), and other study-related materials will be retained in the permanent 
archives of the study site. 
Where permitted by local laws and regulations, records may be maintained in a format other than 
hard copy (e. g., electronically in an electronic medical records system). The Investigator must 
ensure that all reproductions are an accurate legible copy of the original and that they meet 
necessary accessibility and retrieval standards. The Investigator must also ensure that a quality 
control process is in place for making reproductions and that the process has an acceptable back-
up of any reproductions. 


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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 25 years. If the Investigator 
withdraws from the study (e. g., relocation, retirement) all study-related records should be 
transferred, in a written agreement with Indivior, to a mutually agreed upon designee within 
Indivior-specified timeframe. 


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16 AUDITING AND MONITORING 
The purpose of an audit or regulatory inspection is to verify the accuracy and reliability of 
clinical study data submitted to a regulatory authority in support of research or marketing 
applications, and to assess compliance with statutory requirements regulations governing the 
conduct of clinical studies. 
In accordance with applicable regulations, GCP and Indivior procedures, the clinical monitor(s) 
will periodically contact the site, including conducting on-site visits at intervals agreed by the 
Investigator and documented in the Clinical Monitoring Plan and the Site Initiation Visit Report. 
The clinical monitor(s) will contact the site prior to the start of the study to discuss the protocol 
and data collection procedures with site personnel. In accordance with applicable regulations and 
GCP guidelines, the Investigator shall make available for direct access all study-related records 
upon request by Indivior, Indivior’s agents, clinical monitor(s), auditors and/or IRB. The 
monitors will visit the site during the study in addition to maintaining frequent telephone and 
written communication. The extent, nature, and frequency of on-site visits will be based on such 
considerations as the study objectives and/or endpoints, the purpose of the study, study design 
complexity and enrolment rate. 
The Investigator must allow the clinical monitor(s) direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the clinical monitor(s) to discuss findings and 
any relevant issues. 
Upon completion of the study, study closeout activities must be conducted by Indivior or its 
designee in conjunction with the 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, and periodic monitoring visits by Indivior (or 
designee’s). Written instructions will be provided for IMP preparation and dosing, collection, 
preparation and shipment of blood, plasma and urine samples. Guidelines for CRF completion 
will be provided and reviewed with study personnel before the start of the study. Indivior (or 
designee) will review CRFs for accuracy and completeness during on-site monitoring visits and 
after transmission to Indivior (or designee). Any discrepancies will be resolved with the 
Investigator or suitably qualified designee, as appropriate. 
This study will be organized, performed and reported in compliance with the protocol, SOPs, 
working practice documents and applicable regulations and guidelines. 
In accordance with the standards defined in Indivior SOPs and applicable regulatory 
requirements, clinical studies sponsored by Indivior are subject to Indivior Quality Assurance 
(QA) Investigator Site Audits that may be delegated to a Contract Research Organization or 
Indivior contract auditors. Investigator Site Audits will include review of, but are not limited to, 
drug supply, presence of required documents, the informed consent process and comparison of 
CRFs with source documents. The Investigator agrees to participate with audits conducted at a 


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reasonable time in a reasonable manner. Full consultation with the Investigator will be made 
prior to and during such an audit, which will be conducted according to Indivior's or a Contract 
Research Organization's QA SOPs. In addition, this study is subject to inspections by Regulatory 
Authorities. If such a regulatory inspection occurs, the Investigator agrees to allow the regulatory 
inspector direct access to all relevant study documents. The Investigator must contact Indivior 
immediately if this occurs and must fully cooperate with the inspection conducted at a reasonable 
time in a reasonable manner. 
 


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


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18 STUDY REPORTS AND PUBLICATIONS 
A CSR will be prepared following completion of the study. An Investigator signatory may be 
identified for the approval of the report if required by applicable regulatory requirements. 
The study data will be owned by Indivior. Publication of any and all data will be at the discretion 
of Indivior. The Investigator will not disseminate, present or publish any of the study data 
without the prior written approval from Indivior to do so. 
 


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


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20 CONFIDENTIALITY 
All subject-identifying documentation generated in this study is confidential and may not be 
disclosed to any persons not directly concerned with the study without written permission from 
the subject. However, authorized regulatory officials and Indivior personnel (or their 
representatives) will be allowed full access to inspect and copy the records. All subject bodily 
fluids and/or other materials collected shall be used solely in accordance with this protocol and 
the ICF signed by the subject, unless otherwise agreed to in writing by Indivior. 
Each subject will be identified by an assigned subject number when reporting study information 
to any entity outside of the study centre. During the blinded portion of the study, if use of the 
subject number could be unblinding, false or ‘dummy’ subject identifiers may be used. Data 
containing subject identification will not be removed from the study centre without first 
redacting subject identifiers. In the case of the need for remote clinical monitoring, additional 
processes could be developed to allow for the secured electronic provision of unredacted source 
documentation to the clinical monitors.  These will be defined within the Clinical Monitoring 
Plan. 


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21 REFERENCES 
Bonaventure P, Dugovic C, Shireman B, Preville C, Yun S, Lord B, Nepomuceno D, 
Wennerholm M, Lovenberg T, Carruthers N, Fitz SD, Shekhar A, Johnson PL. Evaluation of 
JNJ-54717793 a novel brain penetrant selective Orexin 1 receptor antagonist in 2 rat models of 
panic attach provocation. Front Pharmacol. 2017;8, 357. 
De Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, 
Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe 
JG. The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl 
Acad Sci USA. 1998;95, 322-327. 
Fals-Stewart W, O’Farrell TJ, Freitas TT, McFarlin SK, Rutigliano P. The timeline followback 
reports of psychoactive substance use by drug abusing patients: psychometric properties. J 
Consult Clin Psychol. 2000. 68(1):134-44. 
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubenstein KJ, Kanof PD (1987). Two new 
rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13:293-308. 
Harris GC, Wimmer M, Aston-Jones, G. A role for lateral hypothalamic orexin neurons in 
reward seeking. Nature. 2005;437, 556-559. 
Human Protein Atlas: HCRTR1 (https://www. proteinatlas. org/ENSG00000121764-
HCRTR1/tissue) 2009. Accessed 05 May 2023. 
James LP1, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and 
acute liver failure. Drug Metab Dispos. 2009; 37(8):1779-84 
Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, Träskman-Bendz L, 
Goddard AW, Brundin L, Shekhar A. A key role for Orexin in panic anxiety. Nat Med. 2010;16, 
111-115. 
Kukkonen J and Leonard C. Orexin/hypocretin receptor signalling cascades. Br J Pharmacol. 
2013;171, 314-331. 
McMillan DE, Gilmore-Thomas K. Stability of opioid craving over time as measured by visual 
analogue scales. Drug Alcohol Depend. 1996;40:235-9. 
Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G. Multiple roles for 
orexin/hypocretin in addiction. Prog Brain Res. 2012;198, 79-121. 
Marcus J. Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK. 
Differential expression of Orexin receptors 1 and 2 in the rat brain. J Comp Neurol. 2001;435, 6-
25. 


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Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS. Neurons 
containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18, 9996-
10015. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, et al. The Columbia-suicide severity 
rating scale: initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry. 2011; 168 (12): 1266-77. 
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, 
Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, 
Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ; Yanagisawa M. 
Orexins and Orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled 
receptors that regulate feeding behaviour. Cell. 1998;92, 573-585. 
Soffin EM, Evans MI, Gill CH, Harries MH. SB-334867-A antagonises orexin mediated 
excitation in the locus coeruleus. Neuropharmacology. 2002;42, 127-133. 
Thannickal TC, John J, Shan L; Swaab DF, Wu MF, Ramanathan L, McGregor R, Chew KT, 
Cornford M, Yamanaka A, Inutsuka A, Fronczek R, Lammers GJ, Worley PF, Siegel JM. 
Opiates increase the number of hypocretin-producing cells in human and mouse brain and 
reverse cataplexy in a mouse model of narcolepsy. Sci Transl Med. 2018;10, eaao4953 
The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 
Focused Update. [No authors listed] J Addict Med. 2020 Mar/Apr;14(2S Suppl 1):1-91. 
Thompson M, Xhaard H. Sakurai T. Rainero I. Kukkonen JP. OX1 and OX2 orexin/hypocretin 
receptor pharmacogenetics. Front Neurosci. 2014;8, 1-12. 
Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. Distribution of orexin receptor 
mRNA in the rat brain. FEBS Lett. 1998;438, 71-75. 
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 
2003;35(2):253-9. 
Zarrabian S, Riahi E, Karimi S, Razavi Y, Haghparast A. The potential role of the orexin reward 
system in future treatments for opioid drug abuse. Brain Res. 2018 Nov 23:146028. doi: 10. 
1016/j. brainres. 2018. 11. 023. [Epub ahead of print] Review. PMID: 30476469 
 




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Evaluation 
Screening 
Days 
 -28 to -1 
In clinical unit (Days) 
Discharge Outpatient
Follow-up 
-1 
1 
2 
3 
4 
5 
6 
7 
8  
10 
(± 2 days) 
Day 14/EOS/ET12
(± 3 days) 
Prior or Concomitant Medication 
Assessment
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSSR-S11 
X
X
X
X
X
X
X
1: Check Day -1 Criteria prior to randomization 
2: Discharge occurs after completion of assessments 
3: A full physical examination will be completed at Screening. All other visits will be a brief physical examination consisting of heart, lung, abdomen and 
targeted for any AEs. Pre-dose exam can occur any time pre-AM dose on Day 1, 90 minutes post-Day 1 AM dose (±30 min), Day 2 24 hr post-Day 1 
AM dose (±2 hr), and Day 4 72 hours post-Day 1 AM dose (±2 hr). To be performed also on Day 8 before discharge, and Day 10 72 hours post-Day 7 
AM dose (±2 hr) 
 
For male participants, a testicular exam will be performed at the Screening and End of Study visits.4: Clinical Laboratory Pre-AM dose (-1hr) on Day 1, 
Day 3 and Day 5 and on Day 8 before discharge. 
5: Part I, Cohort 1 (QD): On Day 1, Day 2 and Day 7: pre-dose (-60 min),1 hour post-dose (±30 min), 2 hours post-dose (±30 min), 4 hours post-dose (±30 
min), and 6 hours post-dose (±30 min). On Day 3 and Day 4, vital signs are collected pre-dose (-60 min). On Day 8 vital signs are collected before 
discharge. Triplicate SBP and DBP assessments will be obtained at least 1 minute apart on pre-dose Day 1 and as needed to assess stopping criteria. 
Part I Cohort 2 (BID): On Day 1, and Day 7 (relative to AM dose): pre-dose (-60 min), 1 hour post-dose (±30 min), 2 hours post-dose (±30 min), 4 
hours post-dose (±30 min), 6 hours post-dose (±30 min), 8 hours post-dose (±30 min), 12 hours post-dose (±30 min), 14-16 hours post-dose (±30 min). 
On Day 2, Day 3, and Day 4 vital signs are collected pre-AM dose (-60 minutes). On Day 8 vital signs are collected before discharge. Triplicate SBP 
and DBP assessments will be obtained at least 1 minute apart on pre-AM dose Day 1 and as needed to assess stopping criteria. 
6: On Day 1, Day 2 and Day 7: pre-AM dose (-60 min), 2 hrs post-AM dose (±30 min), and 6 hours post-AM dose (±30 min). On Day 3 and Day 4, ECGs 
are done pre-AM dose (-60 min). Triplicate tracings will be obtained at least 1 minute apart on pre-AM dose Day 1, and as needed to assess stopping 
criteria. 
7: Holter Monitoring 
 
 
8:
 
9: For PK collection timepoints, refer to Section 22.5, Appendix 5 – Plasma PK Sampling Windows. 
10: Part I, Cohort 1 (QD): In house dosing is to occur 24 hr from the previous dose, ±30 min. 
   Part I, Cohort 2 (BID): In house dosing is to occur 12 hours apart, ±30 min. 
11: Lifetime at Screening Visit, the rest of the assessments are the ‘since last visit’ assessment. 
12: Male participants will complete a safety phone call 90 days (±10 days) after their last dosing day to assess any new pain, swelling, or nodular lesions in 
the scrotum. If findings are noted, these will be recorded as AEs and followed until completion of required assessments.


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22.2 APPENDIX 2 – Schedule of Events Part II 
 
Evaluation 
Screening 
Days 
 -28 to -1 
In Clinical Unit (Days)
Discharge
Outpatient (Days)
Follow-up
-1 
1 
2 
3 
4 
5 
6 
7 
8  
10 
(±2)  
15 
(±2) 
22 
(±2) 
28 
(±2) 
Day 
35/EOS/ET12 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to Clinical 
Unit1
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 PCR Test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from 
Clinical Unit2
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Demographics 
(Includes height, 
weight and BMI)
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination3 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Urine Drug Screen
X
X
Alcohol test
X
X
Serum Pregnancy Test
X
X
Urine Pregnancy Test
X
X
X
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
Clinical Laboratory 
Assessments 
(Chemistry and 
Haematology) 
X 
X 
X4 
 
X4 
 
X4 
 
 
X4 
X4 
X4 
X4 
X4 
X 
Serology (HIV, 
Hepatitis B and C) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Panel 
(PT/INR)
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (post-menopausal 
females only)
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X
X
X5
X5
X5
X5
X
X5
X5
X5
X5
X5
X




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10: In house dosing on Days 1 through 8 inclusive is to occur every 12 hours, ±30 mins. Outpatient dosing will continue twice daily every 10-12 hours (±30 
mins) until the final dose on Day 28. Subjects will only dose once on Day 28, in clinic. On days where the subject returns to the clinical unit, the subject 
will be instructed to take their first dose while in the clinic. On days when the subject is dosing at home, they will be instructed to capture each time and 
dose they took in their dosing diary. 
11: Lifetime at Screening Visit, the rest of the assessments are the ‘since last visit’ assessment. 
12: Male participants will complete a safety phone call 90 days (±10 days) after their last dosing day to assess any new pain, swelling, or nodular lesions in 
the scrotum. If findings are noted, these will be recorded as AEs and followed until completion of required assessments.


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22.3 APPENDIX 3 – Schedule of Events Part III 
22.3.1 
Part III - Screening and SUBOXONE SL Film Run-In 
 
Evaluation 
Screening  
SUBOXONE Sublingual Film  
(In clinical unit) 
Induction 
 (3 days) 
Dose-Adjustment 
(3 days) 
Days 
-35 to -7 
Day 
-6 
Day 
-5 
Day 
-4 
Day 
-3 
Day 
-2 
Day 
-17 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
COVID-19 PCR Test
X
Admission to Clinical Unit1 
 
X 
 
 
 
 
 
Demographics (Includes height, weight and BMI)
X
Medical History
X
Physical Examination2 
X 
 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
Alcohol test
X
X
Serum Pregnancy Test
X
Urine Pregnancy Test 
 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
Clinical Laboratory Assessments (Chemistry and Haematology) 
X 
X3 
 
 
 
 
 
Serology (HIV, Hepatitis B and C)
X
Coagulation Panel (PT/INR) 
X 
 
 
 
 
 
 
FSH (post-menopausal females only)
X
Vital Signs 
X
X4
X4
X4
X4
X4
X4
12-Lead Electrocardiogram  
X 
 
 
 
 
 
 
SUBOXONE SL film Administration5 
X
X
X
X
X
X       
AE Assessment
X
X
X
X
X
X


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Evaluation 
Screening  
SUBOXONE Sublingual Film  
(In clinical unit) 
Induction 
 (3 days) 
Dose-Adjustment 
(3 days) 
Days 
-35 to -7 
Day 
-6 
Day 
-5 
Day 
-4 
Day 
-3 
Day 
-2 
Day 
-17 
Concomitant Medication Assessment
X
X
X
X
X
X
C-SSRS6 
X 
 
 
 
 
 
 
1: Confirm Check-In Criteria (defined in Section 5.4) prior to admission to the unit. 
2: A full physical examination will be completed at Screening. For male participants, a testicular exam will be performed.  
3: Clinical Laboratory Assessments are conducted pre-dose (-1 hr). 
4: To be conducted pre-dose (-30 mins), and then at 2 hours (±30 mins) 
5: Administer per the USPI. 
6: Lifetime assessment to be completed during screening. 
7: Day -1 procedures on this table are to be conducted prior to Run-In Assessment criteria on next table 
 
 


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22.3.2 
Part III – Schedule of Events 
Evaluation 
In clinical unit (Days) 
 
Follow-up 
EOS/ET 
(± 3 days) 
-1 
1  
2 
3 
4 
5 
6 
7 
8  
9 
10 
11 
12 
13 
14 
21 
Discharge from Clinical Unit
X1 
Run-In Assessment2 
X
SUBOXONE SL film3 Administration
X
X
X
X
X
X
X
X
X
INDV-2000 Administration
X
X
X
X
X
X
X
X
X
X
X
PK Sampling4 
X
X
X
X
X
X
Physical Examination5
X
X
X
X
X
X
X
Urine Drug Screen
X
X
X
X
Alcohol test
X
X
X
Urine Pregnancy Test
X
X
X
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Clinical Laboratory Assessments (Chemistry and 
Haematology)6 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Vital Signs7 
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram8 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
C-SSRS13 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
AE Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1: Discharge occurs the morning of Day 14 and the clinical facility will provide the subject with options for their continued treatment for OUD. 
2: Subjects must meet Run-In assessment criteria (defined in Section 5.4) on Day -1 prior to completing subsequent Day -1 procedures within this table. 
3: Dose after INDV-2000 AM dose. 
4: For PK collection timepoints, refer to Section 22.5, Appendix 5 – Plasma PK Sampling Windows. 
5: A full physical examination will be completed at Screening; All other visits will be a brief physical examination consisting of heart, lung, abdomen and 


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targeted for any AEs. All timepoints are relative to the AM dose. Pre-dose exam can occur any time pre-dose on Day 2, 90 minutes post-dose (±30 min), Day 5, 9 
and Day 11 pre-dose exam can occur any time pre-AM dose. For male participants, a testicular exam will be performed at the End of Study visit. 
6: Chemistry and haematology to be collected pre-AM dose (-1hr) on Days 3, 9, and 14. Only liver function tests to be collected pre-AM dose on Days 5 and 11. 
7: Vital signs will be completed on Day 1 any time pre-dose, 2 hrs post-dose (±30 min), and 4 hrs post-dose (±30 min) on Days 2, 3, 5, 7, 9, 11, 13. All timepoints 
are relative to the AM dose. Triplicate SBP and DBP assessments will be obtained at least 1 minute apart on pre-dose Day 1 and as needed to assess stopping 
criteria. 
8:12-lead ECG tracing is to be obtained at admission, and on Days 2, 3, 5, 7, 9, 11 and 13 at pre-dose (-1 hr), 2 hrs post-dose (±30 min). All timepoints are relative to 
the AM dose. Triplicate tracings will be obtained at least 1 minute apart on pre-dose Day 1 and as needed to assess stopping criteria. 
13: Baseline assessment to occur at Day -1, all remaining assessments will be ‘Since Last Visit’ CSSR-S. 
 
 


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22.4 APPENDIX 4 – Liver Safety 
The following must occur if a subject meets any of the liver chemistry stopping criteria as 
outlined in Section 6.5 of the protocol: 
 Subject must immediately be withdrawn from treatment. Do not re-challenge with study 
treatment. 
 Notify the Indivior Medical Monitor or specified designee within 24 hours of learning of the 
abnormality. 
 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 must be reported using the SAE Reporting Form (Section 11). 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). 
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: 
 Contact the Indivior Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety. 


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 Subject may continue study treatment, if liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) can be monitored weekly for up to 4 weeks. 
 If the subject later meets the liver chemistry stopping criteria (outlined in  
Section 6.5 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 stopping criteria: 
 Viral hepatitis serology including: 
o Hepatitis A Immunoglobulin M (IgM) antibody, 
o HBsAg and Hepatitis B Core Antibody (IgM), 
o Hepatitis C RNA, 
o Cytomegalovirus IgM antibody, 
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing), and 
o Hepatitis E IgM antibody. 
o Blood sample for PK analysis, obtained within 48 hours of last dose. 
o Serum creatine phosphokinase and lactate dehydrogenase. 
o Fractionate bilirubin, if total bilirubin ≥2x ULN. 
o Assess eosinophilia. 
o 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. 
o Record use of concomitant medications, acetaminophen, herbal remedies, other over-the-
counter medications or putative hepatotoxins on the Concomitant Medications eCRF. 
o Record alcohol use in the eCRF. 
o 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: 


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 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 High-Performance Liquid Chromatography (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 must be 
entered into the eCRF, if these tests are performed. 
 
 


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22.5 APPENDIX 5 –Plasma PK Sampling 
Windows 
 
 


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22.6 APPENDIX 6- Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical 
Trials 
Guidance for 
Industry 
Toxicity Grading Scale for 
Healthy Adult and 
Adolescent Volunteers 
Enrolled in Preventive 
Vaccine Clinical Trials 
 
 
Additional copies of this guidance are available from the Office of Communication, 
Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, 
Rockville, MD 20852- 1448, or by calling 1-800-835-4709 or 301-827-1800, or from the 
Internet at http://www.fda.gov/cber/guidelines.htm. 
 
 
 


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For questions on the content of this guidance, contact the Division of Vaccines and 
Related Products Applications, Office of Vaccines Research and Review at 301-827-3070. 
U.S. Department of Health and Human Services 
Food and Drug 
Administration Center for 
Biologics Evaluation and 
Research 
September 2007 


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Table of Contents 
I. 
INTRODUCTION .....................................................................................................1 
II. 
BACKGROUND .......................................................................................................2 
III. 
TOXICITY GRADING SCALE TABLES ...............................................................2 
A. 
Tables for Clinical Abnormalities ..................................................................3 
B. 
Tables for Laboratory Abnormalities .............................................................6 
IV. 
REFERENCES ..........................................................................................................8 




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FDA’s guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. 
The use of the word should in FDA’s guidances means that something is suggested or 
recommended, but not required. 
 
II. 
BACKGROUND 
Standardized toxicity assessment scales have been widely used to evaluate products treating 
specific diseases. For example, the National Cancer Institute’s Common Toxicity Criteria Scale 
and the Division of AIDS’ Toxicity Grading Scale standardize the evaluation of adverse events 
among patients with cancer and HIV/AIDS, respectively (Refs. 1, 2). The defined toxicity 
parameters in those scales are designed for patients who may already experience mild, moderate, 
or severe adverse clinical or laboratory events due to the disease process, and may not be 
appropriate for healthy volunteers. 
In the development of the toxicity grading scales for healthy volunteers, we chose parameter 
limit values based on published information, when such values were available (Refs. 1-6). For 
example, the Brighton Collaboration has developed case definitions and guidelines to evaluate 
some adverse events associated with administering vaccines (Ref. 3). In some cases, parameter 
limit values were based on clinical experience and experience reviewing vaccine clinical trials 
that enroll normal healthy volunteers. 
Toxicity grading scales for laboratory abnormalities should consider the local laboratory 
reference values when the parameter limit values are defined. The characterization of laboratory 
parameters among some populations of healthy adults and adolescents may require the exercise 
of clinical judgment, for example, consideration of the potential for ethnic differences in white 
blood cell (WBC) counts or gender differences in CPK values. 
III. 
TOXICITY GRADING SCALE TABLES 
Adverse events in a clinical trial of an investigational vaccine must be recorded and monitored 
and, when appropriate, reported to FDA and others involved in an investigation (sponsors, IRBs 
and Investigators). (See, for example, 21 CFR 312.32, 312.33, 312.50, 312.55, 312.56, 312.60, 
312.62, 312.64, 312.66). Although the use of a toxicity grading scale for adverse events would 
not replace these regulatory requirements, using a scale to categorize adverse events observed 
during a clinical trial may assist you in monitoring safety and making required reports. 
Nonetheless, we believe that categorization or grading of data as outlined in this document is 
supplementary to and should not replace full and complete data analysis. 
These guidelines for toxicity grading scales are primarily intended for healthy adult and 
adolescent volunteers. The parameters in the tables below are not necessarily applicable to every 
clinical trial of healthy volunteers. The parameters monitored should be appropriate for the 
specific study vaccine. For some preventive vaccines under development, it may be appropriate 


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to include additional parameters to be monitored during a clinical trial or to alter the choice of 
values in the toxicity table. For example, additional parameters might be added based on one or 
more of the following: safety signals observed in pre-clinical toxicology studies, the biological 
plausibility of the occurrence of certain adverse events, or previous experience with a similar 
licensed product. 
As discussed above, the tables do not represent a recommendation to monitor all the listed 
parameters in all clinical trials of healthy volunteers, nor do the tables represent all possible 
parameters to be monitored. In addition, these tables do not represent study inclusion or 
exclusion criteria. We recommend that the parameters monitored be appropriate for the study 
vaccine administered to healthy volunteers participating in the clinical trial. 
A. 
Tables for Clinical Abnormalities 
Local Reaction to 
Injectable 
Product 
Mild (Grade 1) 
Moderate(Grade 2)
Severe (Grade 3)
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not 
interfere with 
activity 
Repeated use of 
non- narcotic pain 
reliever 
> 24 hours or 
interferes 
with activity
Any use of 
narcotic pain 
reliever or 
prevents 
daily activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort 
with movement 
Significant 
discomfort at 
rest
ER visit or 
hospitalization 
Erythema/Redness * 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling ** 
2.5 – 5 cm and 
does not 
interfere 
with activity
5.1 – 10 cm 
or interferes 
with 
activity
> 10 cm or 
prevents 
daily 
activity
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 


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Vital Signs * 
Mild (Grade 1) 
Moderate(Grade 2)
Severe (Grade 3)
Potentially 
Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
(°F) ** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats 
per minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization 
for 
arrhythmia
Bradycardia - beats 
per minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia
Hypertension (systolic) 
- mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization 
for malignant 
hypertension 
Hypertension (diastolic) 
- mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization 
for malignant 
hypertension 
Hypotension (systolic) 
– mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization 
for hypotensive 
shock
Respiratory Rate – 
breaths 
per minute
17 – 20 
21 – 25 
> 25 
Intubation 
* Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when characterizing 
bradycardia among some healthy volunteer populations, for example, conditioned athletes. 


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Systemic (General) 
Mild (Grade 1) 
Moderate(Grade 2)
Severe (Grade 3)
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference 
with activity or 1 – 
2 episodes/24 hours
Some interference 
with activity or > 
2 episodes/24 
hours 
Prevents daily 
activity, 
requires 
outpatient 
IV hydration
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhoea 
2 – 3 loose stools or
< 400 gms/24 hours
4 – 5 stools or 
400 – 800 
gms/24 hours 
6 or more 
watery stools or 
> 800gms/24 
hours or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non- narcotic pain 
reliever > 24 hours or
some 
interference with 
activity
Significant; 
any use of 
narcotic pain 
reliever or 
prevents 
daily activity
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some 
interference with 
activity
Significant; 
prevents 
daily activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents 
daily 
activity
ER visit or 
hospitalization 
 
Systemic Illness 
Mild (Grade 1) 
Moderate(Grade 2)
Severe (Grade 3)
Potentially Life 
Threatening 
(Grade 4) 
Illness or clinical 
adverse event (as 
defined according to 
applicable 
regulations)
No interference 
with activity 
Some 
interference with 
activity not 
requiring medical 
intervention
Prevents daily 
activity and 
requires 
medical 
intervention
ER visit or 
hospitalization 


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B. 
Tables for Laboratory Abnormalities 
The laboratory values provided in the tables below serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
Serum * 
Mild (Grade 1)
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life
Threatening 
(Grade 4)** 
Sodium – Hyponatremia mEq/L
132 – 134
130 – 131
125 – 129
< 125
Sodium – Hypernatremia mEq/L
144 – 145
146 – 147
148 – 150
> 150
Potassium – Hyperkalemia mEq/L
5.1 – 5.2
5.3 – 5.4
5.5 – 5.6
> 5.6
Potassium – Hypokalemia mEq/L
3.5 – 3.6
3.3 – 3.4
3.1 – 3.2
< 3.1
Glucose – Hypoglycemia mg/dL
65 – 69
55 – 64
45 – 54
< 45
Glucose – 
Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL
 
100 – 110 
110 – 125 
 
111 – 125 
126 – 200 
 
>125 
>200 
Insulin 
requirements or 
hyperosmolar 
coma 
Blood Urea Nitrogen 
BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires 
dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires 
dialysis
Calcium – hypocalcemia mg/dL
8.0 – 8.4
7.5 – 7.9
7.0 – 7.4
< 7.0
Calcium – hypercalcemia mg/dL
10.5 – 11.0
11.1 – 11.5
11.6 – 12.0
> 12.0
Magnesium – hypomagnesemia 
mg/dL
1.3 – 1.5
1.1 – 1.2
0.9 – 1.0
< 0.9
Phosphorous – hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x ULN 
3.1 –10 x ULN 
> 10 x ULN 
Albumin – Hypoalbuminemia g/dL
2.8 – 3.1
2.5 – 2.7
< 2.5
--
Total Protein – Hypoproteinemia 
g/dL
5.5 – 6.0
5.0 – 5.4
< 5.0
--
Alkaline phosphate – 
increase by factor 
1.1 – 2.0 x ULN
2.1 – 3.0 x ULN 
3.1 – 10 x ULN
> 10 x ULN 
Liver Function Tests –ALT, AST 
increase by factor 
1.1 – 2.5 x ULN
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN 
Bilirubin – when accompanied 
by any increase in Liver Function 
Test increase by factor 
1.1 – 1.25 x 
ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x 
ULN 
> 1.75 x ULN 
Bilirubin – when Liver Function 
Test 
is normal; increase by factor
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
Cholesterol
201 – 210
211 – 225
> 226
---
Pancreatic enzymes – amylase, 
lipase
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 5.0 x ULN
> 5.0 x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls 
within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if the subject 
had a new seizure associated with the low sodium value. 
***ULN” is the upper limit of the normal range. 


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Hematology * 
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe (Grade 
3) 
Potentially 
Life 
Threatening 
(Grade 4) 
Hemoglobin (Female) - gm/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female) 
change from baseline value - 
gm/dL
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL
12.5 – 13.5
10.5 – 12.4
8.5 – 10.4
< 8.5
Hemoglobin (Male) 
change from baseline value – 
gm/dL
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm3
10,800 – 15,000
15,001 – 20,000
20,001 – 25, 000
> 25,000
WBC Decrease - cell/mm3
2,500 – 3,500
1,500 – 2,499
1,000 – 1,499
< 1,000
Lymphocytes Decrease -
cell/mm3
750 – 1,000
500 – 749
250 – 499
< 250
Neutrophils Decrease - cell/mm3
1,500 – 2,000
1,000 – 1,499
500 – 999
< 500
Eosinophils - cell/mm3
650 – 1500
1501 - 5000
> 5000
Hypereosinophilic
Platelets Decreased - cell/mm3
125,000 –
140,000
100,000 – 124,000
25,000 – 99,000
< 25,000
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 x 
ULN** 
1.11 – 1.20 x ULN 1.21 – 1.25 x 
ULN 
> 1.25 ULN 
PTT – increase by 
factor (partial 
thromboplastin time)
1.0 – 1.2 x ULN 
1.21 – 1.4 x ULN 
1.41 – 1.5 x ULN > 1.5 x ULN 
Fibrinogen increase - mg/dL
400 – 500
501 – 600
> 600
--
Fibrinogen decrease - mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or 
associated with 
gross bleeding 
or disseminated 
intravascular 
coagulation (DIC)
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** “ULN” is the upper limit of the normal range. 
Urine * 
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe (Grade 3) Potentially 
Life 
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or
dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization 
for 
hyperglycemia
Blood 
(microscopic) – 
red blood cells 
per 
high power field (rbc/hpf)
1 - 10 
11 – 50 
> 50 and/or 
gross blood 
Hospitalization 
or packed red 
blood cells 
(PRBC) 
transfusion 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 


INDV-2000 
 
Indivior 
Clinical Study Protocol: INDV-2000-102 
 
09 May 2023 
 
Confidential 
Page 108 of 108
 
IV. REFERENCES 
2. National Cancer Institute Common Toxicity Criteria, April 30, 1999. 
(http://ctep.cancer.gov/reporting/CTC-3.html) 
3. Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 1992. 
(http://rcc.tech-res-intl.com/tox_tables.htm) 
4. The Brighton Collaboration. Finalized Case Definitions and Guidelines. 
(http://brightoncollaboration.org/internet/en/index/definition  
guidelines.html) 
5. HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; September 
18, 2002. (http://rcc.tech-res-intl.com/tox_tables.htm) 
6. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
December 2004. 
(http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAIDSAEGra 
dingTable.pdf) 
7. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. New 
England Journal of Medicine. 2004;351:1548-1563. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN: INDV-2000-102 
Parts I & II
Protocol Title:  A Phase I Double-Blind, Placebo-Controlled 
Randomized Study to Assess Repeated Doses of INDV-2000 
(C4X_3256) up to 28 Days in Healthy Volunteers, and an Open-Label 
Study of INDV-2000 up to 11 Days in Treatment Seeking Individuals 
with Opioid Use Disorder 
Final Version: 06 Oct 2022
NCT: NCT04976855 


 
 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
Statistical Analysis Plan 
 
Protocol Title:  
A Phase I Double-Blind, Placebo-Controlled Randomized 
Study to Assess Repeated Doses of INDV-2000 (C4X_3256) 
up to 28 Days in Healthy Volunteers, and an Open-Label Study 
of INDV-2000 up to 11 Days in Treatment Seeking Individuals 
with Opioid Use Disorder 
Protocol Number:    
INDV-2000-102 
Compound Number:  
INDV-2000 (C4X_3256) 
Sponsor Name:  
 
Indivior 
Legal Registered Address:  10710 Midlothian Turnpike, Suite 125 
North Chesterfield, VA 23235 
USA 
IND Number: 
 
145881 
Protocol Version: 
 
Amendment 3.0, Version 4.0 
Date:  
 
 
28 July 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential.  Do not copy, 
circulate, or otherwise distribute without written authorization from  
Indivior Inc. 


 
 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
Statistical Analysis Plan Approval  
 


 
 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
TABLE OF CONTENTS 
 
LIST OF TABLES .....................................................................................................................5 
LIST OF FIGURES ...................................................................................................................5 
1. INTRODUCTION .................................................................................................................6 
VERSION HISTORY ................................................................................................................6 
1.1. Objectives and Endpoints ...................................................................................................6 
1.2. Study Design .......................................................................................................................9 
2. STATISTICAL HYPOTHESES ..........................................................................................10 
2.1. Multiplicity Adjustment ....................................................................................................10 
3. SAMPLE SIZE DETERMINATION ..................................................................................10 
4. POPULATIONS FOR ANALYSIS .....................................................................................10 
5. STATISTICAL ANALYSES ..............................................................................................10 
5.1. General Considerations .....................................................................................................10 
5.1.1. Timing of Analyses ..................................................................................................10 
5.1.2. Programming Environment ......................................................................................11 
5.1.3. Reporting Conventions ............................................................................................11 
5.1.4. General Analysis Conventions .................................................................................11 
5.1.5. Definitions................................................................................................................11 
5.2. Study Conduct and Participant Disposition ......................................................................12 
5.3. Primary Endpoints Analysis .............................................................................................12 
5.3.1. Definition of Endpoints ............................................................................................12 
5.3.2. Main Analytical Approach .......................................................................................13 
5.4. Secondary Endpoints Analysis .........................................................................................13 
5.4.1. Definition of Endpoints ............................................................................................13 
5.4.2. Main Analytical Approach .......................................................................................13 
5.5. Exploratory Endpoints Analysis .......................................................................................13 
5.5.1. Definition of Endpoints ............................................................................................13 
5.5.2. Main Analytical Approach .......................................................................................14 
5.6. Other Safety Analyses.......................................................................................................14 
5.6.1. Extent of Exposure and Treatment Compliance ......................................................14 
5.6.2. Adverse Events ........................................................................................................15 
5.6.3. Additional Safety Assessments ................................................................................16 


 
 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
5.6.3.1. Laboratory Data ..............................................................................................16 
5.6.3.2. Vital Signs .......................................................................................................17 
5.6.3.3. Electrocardiogram (ECG) Data .......................................................................18 
5.6.3.4. Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................18 
5.6.3.5. 
 .........................................................18 
5.7. Other Analyses ..................................................................................................................19 
5.7.1. Demographic and Baseline Characteristics .............................................................19 
5.7.2. Medical History .......................................................................................................19 
5.7.3. Prior and Concomitant Medications and Therapies .................................................19 
5.7.4. Protocol Deviations ..................................................................................................19 
5.8. Interim Analyses ...............................................................................................................19 
6. SUPPORTING DOCUMENTATION .................................................................................19 
6.1. Appendix 1: List of Abbreviations ...................................................................................20 
6.2. Appendix 2: Changes to Protocol-Planned Analyses .......................................................20 
6.3. Appendix 3: Definition and Use of Visit Windows in Reporting .....................................21 
6.4. Appendix 4: Endpoint Derivations ...................................................................................21 
6.4.1. Pharmacokinetic Endpoints .....................................................................................21 
6.5. Appendix 5: Statistical Methodology Details ...................................................................21 
6.5.1. PK Analysis .............................................................................................................21 
6.5.1.1. Concentration ..................................................................................................21 
6.5.1.2. PK Parameters .................................................................................................22 
6.6. Appendix 6: Methods to Manage Missing Data ...............................................................23 
6.6.1. BLQ PK Concentrations ..........................................................................................23 
6.6.2. Exposure ..................................................................................................................23 
6.6.3. AEs ...........................................................................................................................23 
6.6.4. Medications and Therapies ......................................................................................24 
6.7. Appendix 7: Data Set Descriptions ...................................................................................25 
7. REFERENCES ....................................................................................................................25 
 
 
 


 
 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
LIST OF TABLES 
Table 1 
SAP Version History Summary ..................................................................6 
Table 2   
Study Objectives and Estimands ................................................................7 
Table 3 
Analysis Populations ................................................................................10 
Table 4 
Expected Number of IMP Doses by Study Part .......................................15 
Table 5 
Planned Laboratory Evaluations ...............................................................17 
 
LIST OF FIGURES 
Figure 1. 
Study Schematic .........................................................................................9 
 
 


 
 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
1. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study INDV-2000-102 Parts I and II and is based 
on Protocol Amendment 3/28 July 2022 (Version 4.0). This SAP supersedes the statistical 
considerations stated in the protocol; any differences are identified in Appendix 2 of this 
document. However, major modifications of the primary endpoint definition or its analysis 
will also be reflected in a protocol amendment. Post hoc or unplanned analyses not specified 
in the SAP will be documented in the clinical study report (CSR). 
VERSION HISTORY 
Table 1 
SAP Version History Summary 
 
1.1. Objectives and Endpoints 
Each study objective is presented in Table 2 with associated estimands. Intercurrent events 
occur after treatment starts and either preclude the observation of an endpoint or affect its 
interpretation. For the intercurrent event of study discontinuation, the principal stratum 
strategy will be used for PK endpoints in that only subjects with an adequate amount of PK 
data will be included in the PK population; for all other endpoints, the while-on-treatment 
strategy will be used since data will be collected only up to end of study (EOS) or study 
discontinuation. Other potential intercurrent events in this study are prohibited medications 
and lifestyle restrictions detailed in protocol sections 9.6.2 and 9.6.3, respectively. Possible 
strategies for these intercurrent events are treatment policy (intercurrent event is ignored), 
while on treatment (data collected after the event is ignored), and principal stratum for PK 
endpoints (subject is excluded from the PK population), to be decided by the sponsor on a 
case-by-case basis. 
 
SAP 
Version 
SAP 
Finalization 
Date 
Associated 
Protocol 
Amendment 
Protocol 
Approval  
Date 
Change 
Rationale 
1.0 
 
06Oct2022 
Amendment 
3.0,  
Version 4.0 
 
28Jul2022 
Not Applicable 
 
Original 
version 
 


 
 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
Table 2   
Study Objectives and Estimands 
  
Estimand 
Objective 
Clinical Category 
 
Statistical 
Category 
 
 
Variable/Endpoint 
 
 
Population 
Population-
Level 
Summary 
Primary Objective 
Assess safety and tolerability of INDV-2000 following repeated doses of INDV-2000 in healthy volunteers. 
Adverse Events (AEs) 
Primary 
Incidence, severity, and relatedness of treatment-emergent adverse 
events (TEAEs), serious adverse events (SAEs) and events leading to 
study discontinuation or death. 
Safety 
Categorical 
descriptive 
Secondary Objective 
Characterize the pharmacokinetic (PK) profile following multiple doses of INDV-2000. 
PK 
Secondary 
INDV-2000 maximum plasma concentration (Cmax) following dosing 
on Days 1 and 7 for Part I and on Days 1, 7 and 28 for Part II 
PK 
Numeric 
descriptive 
  
  
INDV-2000 time of maximum plasma concentration (Tmax) following 
dosing on Days 1 and 7 for Part I and on Days 1, 7 and 28 for Part II 
PK 
Medians, 
ranges  
  
  
INDV-2000 area under the plasma concentration-time curve  
(AUC0-τ) following dosing on Days 1 and 7 for Part I and on Days 1, 
7 and 28 for Part II (τ = 12h for BID dosing and 24h for QD dosing) 
PK 
Numeric 
descriptive 
Exploratory Objectives 


 
 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
  
Estimand 
Objective 
Clinical Category 
 
Statistical 
Category 
 
 
Variable/Endpoint 
 
 
Population 
Population-
Level 
Summary 
 
 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
1.2. Study Design 
This is a Phase I study to assess repeated doses of INDV-2000 in healthy volunteers and in 
treatment-seeking individuals with OUD. The study will be conducted in three parts, as 
depicted in Figure 1. This SAP is for Parts I and II only. 
Figure 1. Study Schematic 
  
 
 
 
 
 
 
 
 
 
 
 
Key features of the study design are described below. 
• Parts I and II are randomized, double-blind, placebo-controlled, multiple ascending dose 
studies, with each part consisting of two INDV-2000 dosing cohorts.  
• In each of Parts I and II, 12 healthy volunteers in each cohort (48 subject total) will be 
randomized to INDV-2000 or placebo in a 3:1 ratio using block size 4.  
• Each part of the study will have a 28-day screening period. Total study duration per 
subject, from screening through the end-of-study (EOS) visit, will be approximately 42 
days for Part I and 63 days for Part II. 
• For male subjects, there will be a safety phone call 90 days after last dose to assess any 
new pain, swelling or nodular lesions in the scrotum. 
• Safety and PK evaluations will be done after each cohort. 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
2. STATISTICAL HYPOTHESES 
There will be no statistical inference in this study. All statistics will be descriptive only. 
2.1. Multiplicity Adjustment 
There will be no statistical inference in this study; therefore, there will be no need for 
multiplicity adjustment. 
3. SAMPLE SIZE DETERMINATION 
The sample size for each part of the study is not based on formal power calculations because 
the study is designed to provide preliminary descriptive assessments of the safety, tolerability 
and PK for INDV-2000. The sample sizes used are typical for studies of this nature and 
should be adequate to assess the parameters described. 
4. POPULATIONS FOR ANALYSIS 
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population shown in Table 3 prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures. 
Table 3 
Analysis Populations 
 
5. STATISTICAL ANALYSES 
5.1. General Considerations 
5.1.1. Timing of Analyses 
There will be a blinded review of the safety and PK data after completion of each cohort 
before dose escalation. The safety data review will be conducted by a Data Review and 
Safety Committee (DRSC). The Sponsor team may unblind after the dose escalation decision 
per cohort has been made. Database lock and final production of TFLs will occur after the 
completion of Part II. 
Population 
Description 
Screened 
Subjects who signed informed consent. 
Safety  
Subjects who received at least one dose of investigational 
medicinal product (IMP). Subjects will be summarized 
according to the study treatment received.  
PK 
Subjects who received at least one dose of INDV-2000, have an 
adequate number of PK samples collected to derive any PK 
parameter, and have no protocol deviations that would 
significantly alter plasma concentration of INDV-2000. 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
5.1.2. Programming Environment 
SAS® version 9.4 or higher (SAS Institute, Cary, North Carolina) will be used for statistical 
analyses and the production of Study Data Tabulation Model (SDTM) and Analysis Data 
Model (ADaM) data sets as well as TFLs.  
5.1.3. Reporting Conventions 
Data will be listed and summarized separately for Parts I and II of the study. Data will be 
summarized by dosing cohort for active treatment and for placebo subjects pooled over both 
dosing cohorts. TFL tables of contents, mock-ups, and specifications are provided in a 
separate document from the SAP. The following reporting conventions will be followed: 
• Treatment group names and order in tables and figures (if applicable) will be INDV-2000 
xxx mg QD, INDV-2000 xxx mg BID, INDV-2000 Pooled, Placebo Pooled, and All 
Subjects [actual dose (xxx) is to be determined]. Some tables may omit the INDV-2000 
Pooled and/or All Subjects groups.   
• Tables and figures will present summaries/analyses by study visit and time point, as 
appropriate.  
• Table column headers and figure legends will include subgroup sample sizes (“N = xx”). 
Sample sizes reported as part of descriptive statistics (“n”) will be the number of non-
missing observations. 
• Listings will generally include unique subject identifier (including site identifier), 
assigned or actual treatment, study visit/time point, assessment or collection date/time, 
parameter, and observed value.  
5.1.4. General Analysis Conventions 
Categorical variables will be summarized using frequencies and percentages.  Percentages 
will be reported to one decimal place.  
Continuous variables will be summarized using descriptive statistics (e.g., n, mean, standard 
deviation (SD), distribution percentiles, range). The number of decimal places for minimums 
and maximums will be the same as the source data. The number of decimal places for means, 
medians, and interquartile ranges will be the same as the source data plus one, and the 
number of decimal places for measures of variance will be the same as the source data plus 
two. See Section 6.5 (Appendix 5) for summary statistics and precision specifications for PK 
data. 
Data with qualifiers (e.g., “<”) will be listed with but summarized without the qualifier. 
5.1.5. Definitions 
IMP: INDV-2000 or placebo 
Screening Period: Informed consent to Day -1 Clinic Check-In. 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
End-of-Study (EOS): Early termination or completion of last scheduled visit. 
Study Day 1: day of first dose of IMP administered in the clinical unit. 
Study day:  
• Study day = date of assessment – date of Study Day 1 + 1, for assessments on or after 
Study Day 1 
• Study day = date of assessment – date of Study Day 1, for assessments before Study Day 
1 
Study time: time of assessment – time of first study drug administered in the clinical unit. 
Duration:  
• Duration in days = end date – start date + 1 
• Duration in minutes = end time – start time. Durations will be adjusted for Daylight 
Saving Time, where applicable. 
Baseline observation: for a given parameter for a given subject, the last observed value, 
including unscheduled and repeated assessments, before the first dose of IMP or planned first 
dose of IMP if IMP was not administered, unless otherwise specified (see Sections 5.6.3.2 
and 5.6.3.3). 
5.2. Study Conduct and Participant Disposition 
Subject disposition summaries will include the number of subjects who were screened for 
Parts I and II, who were randomized, who were in each analysis population, and who 
completed the study. For percentages, the number of subjects screened will be the 
denominator for subjects randomized; the number of subjects randomized will be the 
denominator for the analysis populations and for subjects completing the study. 
Reason for study discontinuation will be summarized by number and percentage of subjects 
for each reason reported; for the percentage, the number of subjects who discontinued will be 
the denominator. 
Reason for screen failure will be summarized in a separate table by number and percentage 
of subjects for each reason reported; the denominator will be the number of screen failures. 
5.3. Primary Endpoints Analysis 
5.3.1. Definition of Endpoints 
The primary endpoints are incidence of TEAEs, maximum severity TEAEs, TEAEs related 
to IMP, treatment-emergent serious adverse events (TESAEs), and TEAEs leading to study 
discontinuation or death.  


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
5.3.2. Main Analytical Approach 
Estimand strategy: While on treatment. 
Analysis set: Safety (see Table 3).   
Analysis methodology:  Descriptive only.  
Intercurrent events and missing data:  AE data will no longer be collected on subjects who 
discontinue early from the study. See Section 6.6.3 (Appendix 6) for details on handling of 
missing AE information.  
See Section 5.6.2 for details on AE summaries and listings. 
5.4. Secondary Endpoints Analysis 
5.4.1. Definition of Endpoints 
The secondary endpoints are: 
• INDV-2000 Cmax following dosing on Days 1 and 7 (Part I) or on Days 1, 7, and 28 (Part 
II) 
• INDV-2000 Tmax following dosing on Days 1 and 7 (Part I) or on Days 1, 7, and 28 (Part 
II) 
• INDV-2000 AUC0-τ following dosing on Days 1 and 7 (Part I) or on Days 1, 7, and 28 
(Part II) 
5.4.2. Main Analytical Approach 
Estimand strategy: Principal stratum. 
Analysis set: PK (see Table 3).   
Analysis methodology:  Standard non-compartmental methods based on actual sampling 
times. Summaries will be descriptive only. See Section 6.4.1 (Appendix 4). 
Intercurrent events and missing data:  Subjects with intercurrent events may be excluded 
from the PK Population, to be decided by the sponsor on a case-by-case basis. See Section 
6.6.1 (Appendix 6) for details on handling of missing data. 
5.5. Exploratory Endpoints Analysis 
5.5.1. Definition of Endpoints 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
5.5.2. Main Analytical Approach 
5.6. Other Safety Analyses 
5.6.1. Extent of Exposure and Treatment Compliance 
IMP exposure will be summarized for the Safety Population as total number of doses, dose 
duration (days), percentage of expected number of doses (%), and number and percentage of 
subjects with number of doses less than 80% of expected. Expected number of doses for each 
part of the study is shown in Table 4. For Part II, percentage of expected number of doses 
and number and percentage of subjects with number of doses less than 80% of expected will 
be summarized both overall and separately for in-clinic vs. outpatient dosing; for outpatient 
dosing, this will be a measure of compliance since this is the only period of the study for 
which IMP is self-administered. 
 
 
 
 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
Table 4 
Expected Number of IMP Doses by Study Part 
Study Part 
Expected Number of IMP Doses 
Part I, Cohort 1 
7 
Part I, Cohort 2 
14 
Part II 
55: 19 in-clinic, 36 outpatient 
5.6.2. Adverse Events 
A TEAE is an AE that started at or after first administration of IMP. 
AEs will be coded to a System Organ Class (SOC) and Preferred Term (PT) using Medical 
Dictionary for Regulatory Activities (MedDRA). Additional details of the coding process, 
including the current version of the dictionary, are described in the Data Management Plan.  
All AEs will be listed for individual subjects. Listings will include SOC, PT, and reported 
term; onset date and time, end date, and duration; treatment-emergence, severity, toxicity 
grade, seriousness and seriousness criteria; relationship to and action taken with IMP; 
whether concomitant treatment was given; outcome; and whether the AE resulted in study 
discontinuation. Duration (days) is calculated as the AE end date – the AE onset date +1; for 
ongoing AEs, the date of end of study participation will be used as the end date. Duration 
will be missing if either the start or end date is partially or completely missing. TESAEs, 
TEAEs leading to IMP discontinuation or interruption, and fatal TEAEs will be listed 
separately. 
The incidence and number of all TEAEs, TESAEs, IMP-related TEAEs and TESAEs, severe 
TEAEs, TEAEs with grade 3 or higher toxicity grade, TEAEs leading to IMP discontinuation 
or interruption, and fatal TEAEs will be presented in an overall summary table.  
TEAEs, TESAEs, IMP-related TEAEs and TESAEs will be summarized by MedDRA SOC 
and PT, each in descending order of frequency among all subjects within study part (then 
alphabetically in case of ties). TEAEs will also be summarized by maximum severity and by 
maximum toxicity grade within SOC and PT. If an AE is reported more than once by a 
subject within a SOC and/or PT, the maximum reported level of severity/toxicity will be used 
at each level of summation in the severity/toxicity summary table.  
Incidence and number of TEAEs will also be summarized by PT only (ie, not SOC), sorted 
by descending frequency among all subjects (within study part). 
Non-TEAEs are defined as AEs that started before first administration of IMP. Non-TEAEs 
will be summarized for randomized subjects. 
See Section 6.6.3 (Appendix 6) for details on handling of missing AE information. 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
5.6.3. Additional Safety Assessments 
5.6.3.1. Laboratory Data 
Planned laboratory evaluations (Table 5) will be summarized by analysis visit as observed 
values and, for numeric values, changes from baseline. Normal/abnormal shifts from baseline 
will also be summarized. Abnormal laboratory evaluations will be listed separately. 
Laboratory evaluations done only at screening will be listed but not summarized. Reported 
values of clinical laboratory parameters that include qualifiers (ie, <, ≤, >, ≥) will be listed as 
reported but will be summarized without the qualifier. 
 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
Table 5 
Planned Laboratory Evaluations 
Haematology 
Haematocrit 
Haemoglobin 
Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with differential (absolute count) 
 
Urinalysis: 
Appearance 
Bilirubin 
Colour 
Glucose 
Ketones 
Leucocyte esterase 
Microscopic examination of sedimenta 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Pregnancy: 
Serum hCG 
Urine hCG 
 
Molecular 
PCR for COVID-19 
 
Screening Only: 
FSH (as needed in post-menopausal females only) 
Haemoglobin A1c 
Hepatitis B surface Antigen 
Hepatitis C Antibody 
HIV-1 and -2 antibodies 
Prothrombin Time with INR 
PTT  
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase 
Gamma-glutamyl transferase 
Glucose (non-fasting) 
Lactate dehydrogenase 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
 
Urine Drug Screen (UDS): 
Opioids 
Cocaine 
Amphetamines 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 
Ethanol 
In addition to the above, for Part III: 
Fentanyl 
Oxycodone 
 
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; 
INR = international normalized ratio; and PTT = partial thromboplastin time. 
a 
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation 
are positive (microscopic examination may include but is not limited to White Blood Cell count, Red Blood 
Cell count, casts and crystals).  
5.6.3.2. Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, temperature) 
will be summarized as observed values and changes from baseline by analysis visit and time 
point. For blood pressure, the mean of triplicate measurements will be used for baseline, if 
available. 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
5.6.3.3. Electrocardiogram (ECG) Data 
Numeric 12-lead ECG parameters [heart rate, PR interval, QRS duration, QT interval, 
Fridericia’s corrected QT interval (QTcF)] will be summarized as observed values and 
changes from baseline by analysis visit and time point; the mean of triplicate measurements 
will be used for baseline, if available. ECG interpretation (normal, abnormal not clinically 
significant, abnormal clinically significant) will be summarized by visit and time point as 
shifts from baseline, with baseline interpretation defined as the consensus among triplicate 
assessments, if available; if there is no consensus, the Sponsor will be notified and will 
provide a baseline interpretation based on a review of the data. 
5.6.3.4. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The composite endpoints Suicidal Ideation and Suicidal Behavior will be derived from the 
following 10 binary C-SSRS questions, reordered from the actual scale to facilitate the 
derivation: 
 
Question 1  
Wish to be Dead 
Question 2  
Non-specific Active Suicidal Thoughts 
Question 3  
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Question 4 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Question 5 
Active Suicidal Ideation with Specific Plan and Intent 
Question 6 
Preparatory Acts or Behavior 
Question 7  
Aborted Attempt 
Question 8 
Interrupted Attempt 
Question 9 
Actual Attempt (non-fatal) 
Question 10 
Completed Suicide 
Suicidal Ideation is derived as “yes” if any of Question 1-5 has a “yes” response. Suicidal 
Behavior is derived as “yes” if any of Question 6-10 has a “yes” response. If there are zero 
“yes” responses and at least one question has a missing response, the derived composite will 
be missing. Suicidal Ideation and Suicidal Behavior will be summarized as categorical 
variables by analysis visit. 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
5.7. Other Analyses 
5.7.1. Demographic and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized separately for the safety 
and PK populations, if different. A summary will also be done for screen failures. Parameters 
to be summarized will be age, sex, race, ethnicity, fertility status, height/weight/body mass 
index, and substance use (alcohol, nicotine, xanthine/caffeine) status (never/current/former). 
5.7.2. Medical History 
Relevant medical history will be coded using MedDRA (refer to the Data Management Plan) 
and will be listed for the safety population. 
5.7.3. Prior and Concomitant Medications and Therapies 
Medications and therapies will be collected from screening through EOS and will be coded 
using Anatomical Therapeutic Chemical (ATC) classification codes via the World Health 
Organization Drug Dictionary (WHO-DD). Additional details of the coding process, 
including the current version of the dictionary, are described in the Data Management Plan. 
Prior medications and therapies will be medications/therapies that ended before first 
administration of IMP or were taken by subjects who did not start IMP. All other medications 
and therapies will be considered concomitant. 
Prior medications and therapies will be summarized for randomized subjects. Concomitant 
medications will be summarized for the safety population. The summary of incidence 
(number and percentage of subjects reporting the medication/therapy at least once) will be 
sorted alphabetically by therapeutic class (ATC level 2) and standardized medication/therapy 
name.  
See Section 6.6.4 (Appendix 6) for details on handling missing information on medications 
and therapies. 
5.7.4. Protocol Deviations 
Protocol deviations will be identified and documented prior to database lock and will be 
summarized by category (eg, prohibited medication, out-of-window assessment) and type 
(eg, major, minor), per the Protocol Deviation Plan for the study, for randomized subjects. 
Deviations that occur in subjects who were not randomized, if any, will be summarized 
separately. All protocol deviations will be listed.  
5.8. Interim Analyses  
Not applicable. 
6. SUPPORTING DOCUMENTATION 
 




 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
Protocol: 
SAP: 
 
Added Screened analysis population. 
AUC endpoint described as AUC0-12h or 0-24h 
AUC endpoint described as AUC0-τ, where τ 
= 12h for BID dosing and 24h for QD 
dosing. 
 
6.3. Appendix 3: Definition and Use of Visit Windows in Reporting 
No windowing will be used for summaries. Analysis visits will be visits denoted in the CRF. 
If a participant has more than 1 assessment for a given visit, the most recent non-missing 
assessment will be used for summaries.   
6.4. Appendix 4: Endpoint Derivations 
6.4.1. Pharmacokinetic Endpoints 
6.5. Appendix 5: Statistical Methodology Details 
Statistical programming will be done using SAS version 9.4 (or later) on a Windows 10 
Enterprise (or later) operating system. Plasma PK parameters will be calculated using 
Phoenix™ WinNonlin® (Version 8.3.4, Certara, LP).  
6.5.1. PK Analysis 
6.5.1.1. Concentration 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
6.5.1.2. PK Parameters 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
6.6. Appendix 6: Methods to Manage Missing Data 
6.6.1. BLQ PK Concentrations 
Concentration values that are reported as BLQ will be presented as “BLQ” in concentration 
listings, replaced by 0 for summary statistic calculations and linear-scale plots of 
concentrations, and excluded from semi-logarithmic-scale plots of concentrations.  
 
For derivations of PK plasma parameters, all concentrations that are BLQ prior to the first 
measurable concentration will be set to zero. BLQ values that are between measurable 
concentrations will be set to missing. Measurable concentrations between 2 BLQ values will 
be set to missing. If two or more consecutive BLQ concentrations are followed by 
quantifiable concentrations, these quantified values will be set to missing. If a BLQ 
concentration is followed by a quantifiable concentration, and the quantifiable concentration 
is then followed by two or more consecutive BLQ concentrations, the quantifiable 
concentration will be set to missing. The BLQ values following the last quantifiable time 
points will be set to missing. No concentration estimates will be imputed for missing sample 
values. 
6.6.2. Exposure 
Missing IMP Dosing Information 
All efforts should be made to obtain missing IMP dosing information from the investigator.  If 
data are still missing after all efforts, then total exposure will be missing and the dose will be 
considered missing for the calculation of compliance.  
 
Missing Last Date of IMP Exposure 
All efforts should be made to obtain missing last date of IMP exposure from the investigator.  
If the last date of exposure is still missing after all efforts, then the last available dosing record 
date may be used as the last IMP exposure date for the calculation of exposure duration.  
 
6.6.3. AEs 
Missing AE Severity 
Missing AE severity must be queried until resolution. In the unlikely event that resolution is 
not possible, missing severity will be imputed as “severe” in summaries. 
 
Missing AE Relationship to IMP  
Missing relationship to IMP for a TEAE must be queried until resolution. In the unlikely 
event that resolution is not possible, missing relationship will be imputed as “related” in 
summaries.  
 
Missing AE Seriousness 
Missing AE seriousness must be queried until resolution. Seriousness cannot be imputed as 
“serious” since doing so would affect the reconciliation between the trial database and the 
SAE registry.  
 
 
 
 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
Missing AE Toxicity Grade 
Missing AE toxicity grade must be queried until resolution, where applicable. There will be 
no imputation for missing toxicity.  
 
Missing AE Start Date/Time Information 
Note: partial times will not be recorded in the CRF. 
For the Safety Population, an AE will be considered treatment emergent under the following 
conditions: 
• Missing start year, month, day, time unless it can be deduced from non-missing 
components of AE end date that the AE ended before first IMP. 
 
• Missing start month, day, time if start year is equal to or after year of first IMP, unless it 
can be deduced from non-missing components of AE end date that AE ended before first 
IMP. 
 
• Missing start day and time if start year is after year of first IMP or if start year is equal to 
year of first IMP and month is equal to or after month of first IMP, unless AE end date is 
before date of first IMP. 
 
• Missing start time if start date is on or after date of first IMP. 
6.6.4. Medications and Therapies 
Missing End Date/Time Information 
Note: partial times will not be recorded in the CRF. 
Prior vs. concomitant status will be assigned as follows: 
Non-missing end date, missing end time 
• If end date is before date of first IMP, medication/therapy is prior. 
• If end date is equal to or after date of first IMP, medication/therapy is concomitant. 
Non-missing end year and month, missing end day 
• If end year is before year of first IMP, medication/therapy is prior. 
• If end year is equal to year of first IMP and end month is before month of first IMP, 
medication/therapy is prior. 
• If end year is equal to year of first IMP and end month is equal to or after month of 
first IMP, medication/therapy is concomitant. 
• If end year is after year of first IMP, medication/therapy is concomitant. 
Non-missing end year, missing end month and day 
• If end year is before year of first IMP, medication/therapy is prior. 
• If end year is equal to or after year of first IMP, medication/therapy is concomitant. 


 
 
SAP for Protocol INDV-2000-102 Parts I & II 
INDV-2000 (C4X_3256) 
Missing end year, month, and day 
• Medication/therapy is concomitant if subject was dosed; otherwise, 
medication/therapy is prior. 
6.7. Appendix 7: Data Set Descriptions 
Trial data sets will consist of CRF exports and external data files. External files may be used 
for protocol deviations and data from the central laboratory, for example. 
7. REFERENCES 
None.