Conditions: Opioid Use Disorder
Keywords: healthy volunteers ADME OUD radiolabel metabolism
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: yes

Brief summary:
The purpose of this open label study is to characterise the absorption, metabolism, excretion, and mass balance of \[14C\]-IDV184001AN (\[14C\]-IDV184001) in healthy adult male participants.

Detailed description:
The study is designed as an open label, single-dose study in healthy adult participants for the following reasons:

* Oral administration of IDV184001AN has demonstrated linear PK and thus \[14C\]IDV184001AN will be given as a single dose.
* A comparator is not necessary for the evaluation of the objectives.
* Blinding of the study treatment is not required as there is no comparator.
* Conducting the study in healthy participants mitigates the potential confounding effects of the disease state and concomitant medications.

Arms:
arm 1: \[14C\]IDV184001AN

Interventions: intervention 1: [14C]IDV184001AN
Intervention descriptions: intervention 1: \[14C\]-IDV184001AN 200 mg/\~100 µCi/ 15 g oral suspension

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL: INDV-2000-105 
Protocol Title: A Phase I, Open Label Study to Assess the 
Absorption, Metabolism, Excretion, and Mass Balance of a 
Single dose of Oral [14C]-IDV184001AN in Healthy Adult 
Male Participants 
Protocol Number: INDV-2000-105 
Original Protocol Date: 15 May 2023
NCT: NCT05974046 


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Clinical Study Protocol 
 
PROTOCOL TITLE:  
A Phase I, Open Label Study to Assess the Absorption, Metabolism, Excretion, and Mass Balance 
of a Single dose of Oral [14C]-IDV184001AN in Healthy Adult Male Participants 
Protocol Number: INDV-2000-105 
Product: IDV184001AN + [14C]-IDV184001AN  
Program Name: INDV-2000 
Short Title:  
Absorption, metabolism, excretion, and mass balance study of [14C]-IDV184001 in healthy 
adults 
Study Phase: Phase I 
Acronym: ADME Study 
Sponsor Name: Indivior Inc. 
Legal Registered Address: 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 125 
North Chesterfield, VA 23235 USA 
 
Regulatory Agency Identifier Number(s) 
Registry 
Identifying Number 
IND 
145881 
 
Approval Date:  15 May 2023 
 
 
 
 
 
 
 
 
 


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Sponsor Signatories: 


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MEDICAL MONITOR NAME AND CONTACT INFORMATION 


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CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
Protocol Number: INDV-2000-105 
Protocol Title: A Phase I, Open Label Study to Assess the Absorption, Metabolism, Excretion, 
and Mass Balance of a Single dose of Oral [14C]-IDV184001AN in Healthy Adult Male 
Participants  
The information contained in this protocol and all other information relevant to this study drug 
is the confidential and proprietary information of Indivior, and except as may be required by 
local laws or regulation, may not be disclosed to others without prior written permission of 
Indivior.  
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. My staff and/or I 
will conduct this study as outlined herein, in accordance with the regulations stated in the 
International Council on Harmonisation E6 / Good Clinical Practice (ICH/GCP) guidelines and will 
make a reasonable effort to complete the study within the time designated.  
I agree to ensure all associates, colleagues, and employees delegated to assist with the conduct 
of the study are trained on this study protocol and amendments, and 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 IDV184001AN 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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TABLE OF CONTENTS 
 
MEDICAL MONITOR NAME AND CONTACT INFORMATION ........................................................... 3 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ..................................................................... 4 
TABLE OF CONTENTS....................................................................................................................... 5 
TABLE OF TABLES ............................................................................................................................ 8 
TABLE OF FIGURES .......................................................................................................................... 8 
ABBREVIATIONS .............................................................................................................................. 9 
1 PROTOCOL SUMMARY ............................................................................................................ 11 
1.1 Synopsis............................................................................................................................. 11 
1.2 Schema .............................................................................................................................. 15 
1.3 Schedule of Events (SoE) ................................................................................................... 16 
2 INTRODUCTION ....................................................................................................................... 19 
2.1 Study Rationale ................................................................................................................. 19 
2.2 Background ....................................................................................................................... 20 
2.2.1 
INDV-2000 (IDV184001) .......................................................................................... 20 
2.3 Benefit/Risk Assessment ................................................................................................... 22 
2.3.1 
Risk Assessment ...................................................................................................... 22 
2.3.2 
Benefit Assessment ................................................................................................. 22 
2.3.3 
Overall Benefit-risk Conclusion ............................................................................... 23 
3 OBJECTIVES AND ENDPOINTS ................................................................................................. 24 
4 STUDY DESIGN ........................................................................................................................ 26 
4.1 Overall Design ................................................................................................................... 26 
4.1.1 
Discharge Criteria .................................................................................................... 27 
4.2 Scientific Rationale for Study Design ................................................................................ 27 
4.3 Justification for Dose ........................................................................................................ 28 
4.4 End of Study Definition ..................................................................................................... 28 
4.5 Protocol Deviations ........................................................................................................... 29 
5 STUDY POPULATION ............................................................................................................... 30 
5.1 Inclusion Criteria ............................................................................................................... 30 
5.2 Exclusion Criteria............................................................................................................... 30 
5.3 Lifestyle Considerations .................................................................................................... 32 
5.3.1 
Meals and Dietary Restrictions ............................................................................... 32 
5.3.2 
Caffeine, Alcohol, and Tobacco .............................................................................. 32 


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5.3.3 
Activity .................................................................................................................... 33 
5.4 Screen Failures .................................................................................................................. 33 
5.5 Enrolled Participant .......................................................................................................... 33 
5.6 Early Discontinuation ........................................................................................................ 33 
6 STUDY DRUG AND CONCOMITANT THERAPY ......................................................................... 34 
6.1 Study Drug(s) Administered .............................................................................................. 34 
6.2 Preparation, Handling, Storage, and Accountability ........................................................ 35 
6.2.1 
Drug Administration ................................................................................................ 35 
6.2.2 
Reporting Product Complaints ................................................................................ 36 
6.3 Assignment to Study Intervention .................................................................................... 36 
6.4 Blinding/Masking .............................................................................................................. 36 
6.5 Study Drug Compliance ..................................................................................................... 37 
6.6 Dose Modification ............................................................................................................. 37 
6.7 Treatment Access to Study Drug After the End of the Study ........................................... 37 
6.8 Treatment of Study Drug Overdose .................................................................................. 37 
6.9 Prior and Concomitant Therapy ........................................................................................ 37 
7 DISCONTINUATION/WITHDRAWAL AND STOPPING CRITERIA ............................................... 39 
7.1 Discontinuation from Study and Study Stopping Criteria ................................................. 39 
7.2 Participant Discontinuation/Withdrawal From the Study ................................................ 39 
7.3 Lost to Follow-up .............................................................................................................. 39 
8 STUDY ASSESSMENTS AND PROCEDURES .............................................................................. 41 
8.1 Administrative Procedures ............................................................................................... 42 
8.1.1 
Informed Consent Procedure ................................................................................. 42 
8.1.2 
Inclusion and Exclusion Criteria .............................................................................. 42 
8.1.3 
Medical History/Demography................................................................................. 42 
8.1.4 
Concomitant Medications ....................................................................................... 42 
8.1.5 
Check-in Criteria ...................................................................................................... 42 
8.2 Efficacy and/or Immunogenicity Assessments ................................................................. 42 
8.3 Safety Assessments ........................................................................................................... 42 
8.3.1 
Physical Examinations ............................................................................................. 43 
8.3.2 
Vital Signs ................................................................................................................ 43 
8.3.3 
Electrocardiograms ................................................................................................. 43 
8.3.4 
Clinical Safety Laboratory Tests .............................................................................. 43 
8.3.5 
 ................................................... 44 


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8.4 Adverse Events, Serious Adverse Events, and Other Safety Reporting ............................ 45 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ...................... 48 
8.4.2 
Method of Detecting AEs and SAEs ........................................................................ 49 
8.4.3 
Reporting and Follow-up of AEs and SAEs .............................................................. 49 
8.4.4 
Regulatory Reporting Requirements for SAEs ........................................................ 50 
8.4.5 
Pregnancy ................................................................................................................ 50 
8.5 Pharmacokinetics .............................................................................................................. 51 
8.6 Pharmacodynamics ........................................................................................................... 52 
8.7 Genetics ............................................................................................................................ 52 
8.8 Biomarkers ........................................................................................................................ 52 
8.9 Medical Resource Utilisation and Health Economics ....................................................... 52 
9 STATISTICAL CONSIDERATIONS .............................................................................................. 53 
9.1 Statistical Hypotheses ....................................................................................................... 53 
9.1.1 
Multiplicity Adjustment .......................................................................................... 53 
9.2 Analyses Sets ..................................................................................................................... 53 
9.3 Statistical Analyses ............................................................................................................ 53 
9.3.1 
General Considerations........................................................................................... 53 
9.3.2 
Primary Endpoints Analysis ..................................................................................... 53 
9.3.3 
Secondary Endpoints Analysis ................................................................................ 54 
9.3.4 
Tertiary Endpoints Analysis ..................................................................................... 54 
9.4 Interim Analysis ................................................................................................................. 54 
9.5 Sample Size Determination ............................................................................................... 55 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................. 56 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ...................... 56 
10.1.1 Regulatory and Ethical Considerations ................................................................... 56 
10.1.2 Financial Disclosure ................................................................................................. 56 
10.1.3 Informed Consent Process ...................................................................................... 57 
10.1.4 Data Protection ....................................................................................................... 57 
10.1.5 Dissemination of Clinical Study Data ...................................................................... 57 
10.1.6 Data Quality Assurance ........................................................................................... 58 
10.1.7 Source Documents .................................................................................................. 59 
10.1.8 Study and Site Start and Closure ............................................................................ 59 
10.1.9 Publication Policy .................................................................................................... 60 


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10.2 
Appendix 2: Clinical Laboratory Tests ........................................................................ 60 
10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy Information ...... 62 
10.3.1 Contraception Guidance ......................................................................................... 62 
10.4 
Appendix 4: Pharmacokinetic Sampling Schedule ..................................................... 63 
10.5 
Appendix 5:Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials ......................................................................... 68 
I. 
Introduction ............................................................................................................ 69 
II. 
Background ............................................................................................................. 70 
III. 
Toxicity grading scale tables ................................................................................... 70 
IV. 
References .............................................................................................................. 76 
10.6 
REFERENCES ................................................................................................................ 77 
 
TABLE OF TABLES 
Table 1 
Objectives and Endpoints ........................................................................................... 12 
Table 2 
Study Drug Administered ........................................................................................... 34 
Table 3 
Blood Volume during the Study ................................................................................. 41 
Table 4 
Populations for Analysis ............................................................................................. 53 
Table 5 
Protocol-required Safety Laboratory Tests ................................................................ 61 
Table 6 
Blood PK sampling schedule ....................................................................................... 63 
Table 7 
Urine sampling schedule ............................................................................................ 64 
Table 8 
Fecal sampling schedule ............................................................................................. 65 
Table 9 
List of Whole Blood and Plasma Pharmacokinetic Parameters (non-exhaustive) ..... 66 
Table 10 
List of Urine and Feces Pharmacokinetic Parameters (non-exhaustive) ................... 67 
 
TABLE OF FIGURES 
Figure 1 
Study Schema ............................................................................................................. 15 
Figure 2 
Schedule of Events (SoE) ............................................................................................ 16 
 
 
 


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ABBREVIATIONS 
ADME 
absorption, distribution, metabolism, and elimination 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
aspartate aminotransferase 
AST 
alanine aminotransferase 
 
 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRF 
Case Report Form 
CYP 
cytochrome P450 
DORA 
dual orexin receptor antagonist 
ECG 
electrocardiogram 
EOS 
end of study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
INR 
international normalised ratio 
IRB 
Institutional Review Board 


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LSC 
liquid scintillation counting 
M12 
INDV-2000 demethylated metabolite 
OUD 
opioid use disorder 
OX1R/OX2R 
orexin-1/orexin-2 receptor 
PK 
pharmacokinetic(s) 
QTcF 
heart rate-corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoE 
Schedule of Events 
SOP 
Standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
TRA 
total radioactivity 
ULN 
upper limit of normal 


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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title:  
A Phase I, Open Label Study to Assess the Absorption, Metabolism, Excretion, and Mass Balance 
of a Single dose of Oral [14C]-IDV184001AN in Healthy Adult Male Participants 
Short Title: 
Absorption, metabolism, excretion, and mass balance study of [14C]-IDV184001 in healthy 
adults 
Regulatory Agency Identifier Number(s): 
Registry 
Identifying Number 
IND 
145881 
Rationale:  
The disposition of any drug in the body is controlled by physiological processes affecting 
absorption, metabolism, and excretion. The most efficient and well-established approach to 
elucidate these processes is a mass balance study in which the drug dose is administered in 
radiolabelled form, followed by collection and analysis of different biological matrices. 
Radioactivity will be quantitated using liquid scintillation counting (LSC) and determination of 
drug and metabolite concentrations using conventional liquid chromatography-tandem mass 
spectrometry. 
The purpose of this open label study is to characterise the absorption, metabolism, excretion, 
and mass balance of [14C]-IDV184001*, in healthy adult male participants. 


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* Note: IDV184001 is the active moiety of IDV184001AN. 
Objectives and Endpoints 
Table 1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To investigate the route(s) of elimination 
and the overall mass balance of IDV184001, 
following a single oral dose of 
[14C]-IDV184001AN in healthy adult male 
participants. 
• Total radioactivity (TRA) recovery and the 
percent of the radioactive dose excreted in the 
urine and feces [Time Frame: Pre-dose to 168 
hours post-dose, collection time can be 
extended]. 
• To quantitate TRA in whole blood, plasma, 
urine, and feces following a single oral dose 
of [14C]-IDV184001AN in healthy adult male 
participants. 
• TRA PK parameters in plasma and whole blood: 
AUClast, AUC0-∞, AUCextrap(%), Cmax, Tmax, λz, and 
T1/2 as data permits [Time Frame: Pre-dose to 
168 hours post-dose, collection time can be 
extended]. 
• TRA PK parameters in urine and feces: Aet1-t2, 
CumAe, %Dose, Cum%Dose, and CLr (urine only) 
[Time Frame: Pre-dose to 168 hours post-dose, 
collection time can be extended]. 
• To characterise the PK profile of unlabelled 
IDV184001 and M12 in plasma following a 
single oral dose of [14C]-IDV184001AN in 
healthy adult male participants. 
• Unlabelled IDV184001 and M12 PK parameters 
in plasma: AUClast, AUC0-∞, AUCextrap(%), Cmax, Tmax, 
λz, T1/2, as data permits [Time Frame: Pre-dose 
to 168 hours post-dose]. 
• Ratio of unlabelled IDV184001 and M12 in 
plasma to plasma TRA for AUClast and Cmax, 
where appropriate [Time Frame: Pre-dose to 
168 hours post-dose]. 
• To characterise metabolite identification, 
profiling and quantitation for IDV184001 in 
plasma, urine, and feces following a single 
oral dose of [14C]-IDV184001AN in healthy 
adult male participants. 
• IDV184001 metabolite identification, profiling 
and quantitation in plasma, urine, and fecal 
samples [Time Frame: Pre-dose to 168 hours 
post-dose, collection time can be extended]. 
• To determine the ratio of TRA 
concentration equivalents in whole blood 
• The ratio of TRA concentration equivalents in 
whole blood relative to plasma at each 


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versus plasma following a single oral dose 
of [14C]-IDV184001AN in healthy adult male 
participants. 
time-matched determination of TRA in whole 
blood and plasma [Time Frame: Pre-dose to 
168 hours post-dose, collection time can be 
extended]. 
 
Secondary 
 
• To assess the safety and tolerability of a 
single oral dose of [14C]-IDV184001AN as 
determined by AE reporting. 
• Incidence, seriousness, severity, and relatedness 
of treatment emergent adverse events (TEAEs). 
Tertiary/Exploratory 
Overall Design Synopsis: 
This is an open-label, single-dose study in healthy adult male participants. 
Brief Summary: 
The purpose of this study is to characterise the absorption, metabolism, and excretion, and 
mass balance of [14C]-IDV184001. 
Participants who meet the eligibility criteria will be admitted to the study site on Day -1 and will 
remain confined until at least Day 8 (if at least one discharge criterion is met) or up to a 
maximum stay of 21 days post-dose (ie, Day 22). 
On Day 1, participants will receive a single oral dose of 200 mg (~100 µCi) [14C]-IDV184001AN. 
Blood (for plasma and whole blood), urine, and fecal samples will be collected pre-dose and for 
at least 168 hours post-dose (ie, Day 8) to measure TRA (all sample matrices), and for 
metabolite identification, profiling and quantitation (plasma, urine, and feces), as appropriate. 
Blood samples for plasma concentrations of unlabelled IDV184001 and M12 will also be 
collected pre-dose and for 168 hours post-dose. 
Participants may be discharged from the study site following the 168-hour post-dose blood 
draw and/or study procedures on Day 8, if at least one discharge criterion is met (refer to 
Section 4.1.1). If neither discharge criteria is met by 168 hours post-dose (ie, Day 8), 
participants will remain confined at the study site until at least one discharge criterion is met or 
a maximum stay of 21 days post-dose is reached (ie, Day 22), whichever is first. For participants 
who remain confined past Day 8, collection of urine and fecal samples for TRA determination 
and metabolite identification, profiling and quantitation will continue in 24-hour intervals and 


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collection of blood for TRA determination (whole blood and plasma) and metabolite 
identification, profiling and quantitation (plasma) will continue in 72-hour intervals. 
Participants who terminate the study early will be asked to return to the study site 7±2 days 
after dosing for follow-up procedures, and to determine if any AE has occurred since the last 
study visit. 
Number of Participants: 
Approximately 7 participants will be enrolled to ensure 6 participants complete the study. The 
sample size was selected without statistical considerations. It has been determined adequate to 
meet the study objectives and is in accordance to the FDA guidance (FDA 2022). This sample 
size is limited based on clinical considerations for this type of study and in order to limit 
exposure to radioactivity. 
Note: A participant will be considered enrolled at the time he receives the study drug. 
Study Treatment and Duration: 
On Day 1, participants will receive a single oral dose of 200 mg (~100 µCi) [14C]-IDV184001AN. 
The total planned study duration (screening to EOS) for each participant will be up to 7 weeks. 
This includes a screening period of up to 4 weeks (ie, within 28 days prior to dosing on Day 1) 
and a treatment period of at least 1 week (Days 1 to 8) until at least one discharge criterion is 
met, up to maximum of 3 weeks (Days 1 to 22). Participants who terminate the study early will 
be asked to return to the study site 7±2 days after dosing for follow-up procedures, and to 
determine if any AE has occurred since the last study visit. 
Data Monitoring/Other Committee: No 
 
 


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1.2 
Schema 
Figure 1 
Study Schema 
 
 


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1.3 
Schedule of Events (SoE) 
Figure 2 
Schedule of Events (SoE) 
Study Procedures 1 
Scr 2 
Treatment Period (Days) 
Discharge/
EOS 4 
ET 5 
–1 3 
1 
2 
3 
4 
5 
6 
7 
8 
9-22 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Check-In Criteria 6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
including height and weight 7 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
COVID-19 screen (rapid test) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B, and C (antibody) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Haematology, serum chemistry 8, 
urinalysis 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
Coagulation 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
AE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
[14C]-IDV184001AN dosing 
 
 
X 
 
 
 
 
 
 
 
 
 
 


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Study Procedures 1 
Scr 2 
Treatment Period (Days) 
Discharge/
EOS 4 
ET 5 
–1 3 
1 
2 
3 
4 
5 
6 
7 
8 
9-22 
Blood for unlabelled IDV184001 
and M12 plasma PK 
 
 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
 
 
 
Blood for whole blood TRA 13 
 
 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
 
 
Blood for plasma TRA 13 
 
 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
 
 
Blood for plasma metabolic 
profiling 13 
 
 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
X 12 
 
 
Urine for TRA and metabolic 
profiling 14 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Feces for TRA and metabolic 
profiling 15 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE=adverse event;
 COVID-19=Coronavirus disease 2019; 
 EOS=End of study; ET=early 
termination; HIV=Human immunodeficiency; PK=pharmacokinetic; Scr=Screening; TRA=Total radioactivity  
1. For details on procedures, refer to Section 8. 
2. Within 28 days prior to dosing. 
3. Participants will be admitted to the study site on Day -1, at the time indicated by the study site, and will remain confined until 
Day 8, if at least one discharge criterion is met. If neither discharge criteria is met by Day 8, participants will remain confined at 
the study site until at least one discharge criterion is met or a maximum stay of 21 days post-dose is reached (ie, Day 22), 
whichever is first. 
4. To be conducted prior to the discharge from study unit. Participant will be discharged from the study unit as of Day 8, after at 
least one discharge criterion is met or after the maximum stay of 21 days post-dose, on Day 22. Since an approximate 24-hour 
time lag is anticipated for TRA measurement, actual participant release from the study site may occur 1 day after a discharge 
criterion is met. 
5. Participant who terminate the study early will be asked to return to the study site 7±2 days after dosing for follow-up 
procedures, and to determine if any AE has occurred since the last study visit. 
6. For details on Check-In Criteria, see Section 8.1.5. 
7. Height collected at screening only.  


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8. Samples for serum chemistry will be obtained after a fast of at least 12 hours, however, in case of dropouts or rechecks, 
participants may not have fasted for 12 hours prior to when the serum chemistry sample is taken.  
9. To be collected within 2 hours prior to dosing (pre-dose) and at 1 hour (±20 minutes), 2 hours (±20 minutes), and 4 hours 
(±20 minutes) post-dose. 
10. To be collected within 2 hours prior to dosing (pre-dose) and at 1 hour (±15 minutes), 2 hours (±15 minutes), and 4 hours 
(±15 minutes) post-dose. 
12. For blood sample collection time points, please refer to Section 10.4 (Appendix 4). 
13. Blood samples will be samples will be collected for at least 168 hours post-dose, at the time points indicated. If neither discharge 
criteria (see Section 4.1.1) is met by 168 hours post-dose (ie, Day 8), sampling for TRA determination (plasma and whole blood) 
and metabolite identification, profiling and quantitation (plasma) will continue every 72 hours thereafter, until at least one 
discharge criterion is met or up to a maximum stay of 21 days post-dose (ie, Day 22). 
14. Urine collection for analysis of TRA and metabolite identification, profiling and quantitation will be conducted at the following 
intervals: pre-dose (spot collection), 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours post-dose, and in 24-hour intervals until at least 
168 hours post-dose (ie, Day 8). If neither discharge criteria (see Section 4.1.1) is met by 168 hours post dose (ie, Day 8), urine 
collection will continue in 24-hour intervals thereafter, until at least one discharge criterion is met or up to a maximum stay of 
21 days post-dose (ie, Day 22). 
15. Fecal collection for the analysis of TRA and metabolite identification, profiling and quantitation will be conducted pre-dose 
(within 48 hours pre-dose) and in 24-hour intervals for at least 168 hours post-dose (ie, Day 8). If neither discharge criteria (see 
Section 4.1.1) is met by 168 hours post-dose (ie, Day 8), fecal collection will continue in 24-hour intervals thereafter, until at least 
one discharge criterion is met or up to a maximum stay of 21 days post-dose (ie, Day 22). 
 


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2 INTRODUCTION 
INDV-2000 (also referred to as C4X_3256) is a highly potent and selective OX1R antagonist that 
is being developed as a therapy for the treatment of OUD.  
2.1 Study Rationale 
The disposition of any drug in the body is controlled by physiological processes affecting 
absorption, metabolism, and excretion. The most efficient and well-established approach to 
elucidate these processes is a mass balance study in which the drug dose is administered in 
radiolabelled form, followed by collection and analysis of different biological matrices. 
Radioactivity will be quantitated using LSC and determination of drug and metabolite 
concentrations using conventional liquid chromatography-tandem mass spectrometry. 
The purpose of this open label study is to characterise the absorption, metabolism, excretion, 
and mass balance of [14C]-IDV184001* in healthy adult male participants. 
* Note: IDV184001 is the active moiety of IDV184001AN. 
 


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2.2 Background 
2.2.1 INDV-2000 (IDV184001) 
INDV-2000 is a potent and competitive antagonist of the human OX1R with good selectivity in 
vitro. In humans, the OX1R is expressed in the brain, predominantly in projections from the 
lateral hypothalamus, including the ventral tegmental area and the ventromedial prefrontal 
cortex and it binds the neuropeptide Orexin-A and, with less affinity, Orexin-B. The number of 
Orexin-A producing neurons is increased in the brains of individuals with heroin dependence 
(Thannickal 2018). Antagonism of the OX1R inhibits addiction-related behaviours in non-clinical 
rodent models including self-administration, relapse to drug seeking, and withdrawal 
(Azizi 2010, Mahler 2012, Hooshmand 2017, Dunn 2019). Hence it is hypothesised that OX1R 
antagonists should show clinical benefit in the treatment of substance use disorders, including 
OUD, by reducing craving, relapse, and symptoms of withdrawal. 
There are several selective OX1R antagonists (eg, ACT-539313, JNJ-61393215, AZD4041, 
CVN766) and dual OX1R/OX2R antagonists already in clinical development. BELSOMRA® 
(suvorexant), DAYVIGO® (lemborexant) and QUVIVIQ® (daridorexant) are dual OX1R/OX2R 
antagonists approved for the treatment of insomnia (Coleman 2017, Murphy 2017, Markham 
2022). There have been no published reports of any significant safety issues in animals or 
humans with these compounds. 
The most relevant data on INDV-2000 for the present study are summarised below. A detailed 
description of the chemistry, pharmacology, efficacy, and safety of INDV-2000 is provided in the 
most recent IB.  
Nonclinical summary 
INDV-2000 underwent a comprehensive program of non-clinical pharmacology, PK, and 
toxicology investigations.  


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Clinical summary 
Additional information on PK and safety of INDV-2000 is provided in the most recent IB.  


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2.3 Benefit/Risk Assessment 
Benefit and risk assessment are highlighted below; however more detailed information about 
the known and expected benefits and risks and reasonably expected AEs of INDV-2000 are 
found in the IB. 
2.3.1 Risk Assessment 
Investigational Study Drug:  
Study Procedures: 
A potential risk associated with study procedures are the risks associated with phlebotomy 
since multiple blood samples are collected throughout the study period. However, limits for 
number of samples and sample volumes are in place, according to local guidance. 
2.3.2 Benefit Assessment 
Participants in this clinical study will not receive direct health benefits from study drug during 
participation. An indirect health benefit to the participants enrolled in this study is the free 
medical tests received at screening and during the study. 


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2.3.3 Overall Benefit-risk Conclusion 
This is a study in healthy participants, and there is no direct benefit to study participants. The 
data obtained from this healthy participant study may inform future clinical studies in 
participants with OUD or other indications under study. 
Administration of a single oral dose of 200 mg (~100 µCi) [14C]-IDV184001AN is not expected to 
cause any safety concern in healthy male participants. The estimated total radioactive dose and 
the tissue specific exposure from a single oral administration of ~100 µCi of [14C]-IDV184001AN 
are below the radiation dose limits set forth by the FDA (FDA 2023). Thus, the health risk 
resulting from exposure to radiation in the study drug is very low. 
The study site will follow a risk management plan to minimise the exposure of participants to 
COVID-19. The IRB/ IEC approved COVID-19 clinical pharmacology unit management plan will 
be provided separately. 
The safety monitoring practices employed by this protocol
 
 are adequate to protect 
the participants’ safety and should detect all expected TEAEs. 


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3 OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To investigate the route(s) of elimination 
and the overall mass balance of IDV184001, 
following a single oral dose of 
[14C]-IDV184001AN in healthy adult male 
participants. 
• TRA recovery and the percent of the 
radioactive dose excreted in the urine and 
feces [Time Frame: Pre-dose to 168 hours 
post-dose, collection time can be 
extended]. 
• To quantitate TRA in whole blood, plasma, 
urine, and feces following a single oral dose 
of [14C]-IDV184001AN in healthy adult male 
participants. 
• TRA PK parameters in plasma and whole 
blood: AUClast, AUC0-∞, AUCextrap(%), Cmax, 
Tmax, λz, and T1/2 as data permits [Time 
Frame: Pre-dose to 168 hours post-dose, 
collection time can be extended]. 
• TRA PK parameters in urine and feces: 
Aet1-t2, CumAe, %Dose, Cum%Dose, and 
CLr (urine only) [Time Frame: Pre-dose to 
168 hours post-dose, collection time can 
be extended]. 
• To characterise the PK profile of unlabelled 
IDV184001 and M12 in plasma following a 
single oral dose of [14C]-IDV184001AN in 
healthy adult male participants. 
• Unlabelled IDV184001 and M12 PK 
parameters in plasma: AUClast, AUC0-∞, 
AUCextrap(%), Cmax, Tmax, λz, T1/2, as data 
permits [Time Frame: Pre-dose to 168 
hours post-dose]. 
• Ratio of unlabelled IDV184001 and M12 
in plasma to plasma TRA for AUClast and 
Cmax, where appropriate [Time Frame: 
Pre-dose to 168 hours post-dose]. 
• To characterise metabolite identification, 
profiling and quantitation for IDV184001 in 
plasma, urine, and feces following a single 
oral dose of [14C]-IDV184001AN in healthy 
adult male participants. 
• IDV184001 metabolite identification, 
profiling and quantitation in plasma, 
urine, and fecal samples [Time Frame: 
Pre-dose to 168 hours post-dose, 
collection time can be extended]. 
• To determine the ratio of TRA 
concentration equivalents in whole blood 
versus plasma following a single oral dose 
of [14C]-IDV184001AN in healthy adult male 
participants. 
• The ratio of TRA concentration 
equivalents in whole blood relative to 
plasma at each time-matched 
determination of TRA in whole blood 
and plasma [Time Frame: Pre-dose to 
168 hours post-dose, collection time can 
be extended]. 


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Secondary 
 
• To assess the safety and tolerability of a 
single oral dose of [14C]-IDV184001AN as 
determined by AE reporting. 
• Incidence, seriousness, severity, and 
relatedness of TEAEs. 
Tertiary/Exploratory 


I N D V-2 0 0 0  
Cli nic al St u dy Pr ot oc ol: I N D V -2 0 0 0 -1 0 5 Fi n al  
I n di vi or 
1 5  M a y 2 0 2 3  
 
C o nfi d e nti al  
P a g e 2 6  of 7 8 
4  S T U D Y D E SI G N  
4. 1  O v er all D esi g n  
 
T his is a n o p e n l a b el, si n gl e-d os e  st u d y i n h e alt hy a d ult p artici p a nts. 
 
A p pr oxi m at el y 7 m al e p artici p a nts will b e e nr oll e d t o pr ovi d e at l e ast 6 c o m pl et e d 
p artici p a nts. 
 
T h e t ot al pl a n n e d st u d y d ur ati o n (scr e e ni n g t o E O S) f or e ac h p artici p a nt will b e  u p t o  
7 w e e ks. T his i ncl u d es a scr e e ni n g p eri o d  a n d a tr e at m e nt  p eri o d : 
o  
Scr e e ni n g: D a y -2 8 u p t o d osi n g o n D a y 1 ; 
o  
Tr e at m e nt P eri o d: D a y 1 t o  u p t o m axi m u m  D a y 2 2  
 
D a y - 1: C h ec k -i n at t h e ti m e i n dic at e d b y t h e st u d y sit e, f or eli gi bl e 
p artici p a nts. 
 
D a y 1: P artici p a nts will r ec ei v e a si n gl e or al d os e of 2 0 0 m g ( ~1 0 0 µ Ci ) 
[1 4C]- I D V 1 8 4 0 0 1 A N. 
 
D a ys 2 t o 7 : All p artici p a nts will r e m ai n i n t h e st u d y sit e. 
 
D a y 8- 2 2 : P artici p a nts w h o m e et at l e ast o n e disc h ar g e crit erio n  will b e 
r el e as e d fr o m t h e st u d y sit e st arti n g o n D a y 8 (r ef er t o S ecti o n  4. 1. 1 ). If 
n eit h er disc h ar g e crit eri o n is m et b y D a y 8, p artici p a nt will r e m ai n c o nfi n e d 
u ntil at l e ast o n e disc h ar g e crit eri o n is m et or u p t o a m axi m u m st a y of 2 1 
d a ys p ost -d os e (i e,  D a y 2 2) , w hic h e v er is first. 
 
Disc h ar g e / E O S: C h ec k-o ut fr o m t h e st u d y sit e f oll o wi n g c o m pl eti o n of t h e 
pr oc e d ur es sc h e d ul e d at disc h ar g e ; n ot e t h at a n a p pr oxi m at e 2 4-h o ur ti m e 
l a g is a ntici p at e d f or T R A m e as ur e m e nt, act u al p artici p a nt r el e as e fr o m t h e 
st u d y sit e m a y occ ur 1  d a y aft er a disc h ar g e crit eri o n is m et.  
 
P artici p a nts w h o t er mi n at e t h e st u d y e arly will b e as k e d t o r et ur n t o t h e st u d y 
sit e 7 ± 2 d a ys aft er d osi n g f or f oll o w- u p pr oc e d ur es, a n d t o d et er mi n e if a n y 
A E h as occ urr e d si nc e t h e l ast st u d y visit.  
 
Bl o o d s a m pli n g f or u nl a b ell e d I D V 1 8 4 0 0 1 a n d M 1 2 pl as m a c o nc e ntr ati o ns will b e 
c o n d uct e d pri or t o d osi n g o n D a y 1 a n d f or 1 6 8 h o urs p ost -d os e.  
 
B l o o d s a m pli n g f or w h ol e bl o o d T R A will b e c o n d uct e d f or at l e ast  1 6 8  h o urs p ost -d os e.  If 
n eit h er disc h ar g e crit eri a (s e e S ecti o n  4. 1. 1 ) is m et b y 1 6 8 h o urs p ost -d os e (i e, D ay 8), 
s a m pli n g f or w h ol e bl o o d T R A d et er mi n ati o n will c o nti n u e ev er y 7 2  h o urs t h er e aft er, u ntil 
at l e ast o n e disc h ar g e crit eri o n is m et or u p t o a m axi m u m st a y of 2 1 d a ys p ost -d os e (i e, 
D a y 2 2).  
 
Bl o o d s a m pli n g f or pl as m a T R A pl as m a a n d m et a b olit e i d e ntific ati o n, pr ofili n g a n d 
q u a ntit ati o n will b e c o n d uct e d f or at l e ast 1 6 8 h o urs p ost -d os e. If n eit h er disc h ar g e crit eri a 
(s e e S ecti o n  4. 1. 1 ) is m et b y 1 6 8 h o urs  p ost -d os e (i e, D a y 8), s a m pli n g f or pl as m a T R A 
d et er mi n ati o n a n d m et a b olit e i d e ntific ati o n, pr ofili n g a n d q u a ntit ati o n  will c o nti n u e e v ery 






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4.5 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 participant, the 
Investigator, or the study-site staff. It is the responsibility of the Investigator and study-site staff 
to use continuous vigilance to identify and report deviations to Indivior or specified designee, 
and to the IRB/IEC per local requirements. 


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5 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
Participant must be 19 to 55 years of age inclusive, at the time of signing the 
informed consent. 
2. 
Participant must have body weight of a minimum of 50.0 kg at the Screening Visit 
and body mass index within the range 18.0 to 32.0 kg/m2 (inclusive). 
3. 
Participant must be male and who is healthy as determined by medical evaluation.  
4. 
Participant agrees to follow contraception guidelines in Section 10.3 (Appendix 3). 
5. 
Participant must be continuous non-smoker who has not used nicotine- and 
tobacco-containing products for at least 3 months prior to dosing based on 
participant self-reporting. 
6. 
Participant must be capable of giving signed informed consent as described in 
Section 10.1.3 (Appendix 1) which includes compliance with the requirements and 
restrictions listed in the ICF and in this protocol. 
5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. 
Have an ongoing medical history of clinically significant neurological, cardiovascular, 
renal, hepatic, chronic respiratory or gastrointestinal disease, psychiatric or other 
disorder as judged by an Investigator that could potentially affect the study 
outcomes or compromise participant safety. 
2. 
Have clinically significant abnormal biochemistry, haematology or urinalysis results 
as judged by an Investigator. 
3. 
Have a history of narcolepsy or sleep apnea. 
4. 
Have disorders that may interfere with drug absorption, distribution, metabolism 
and excretion processes. 
5. 
Current active hepatic or biliary disease.  
6. 
Participants with cholecystectomy <90 days prior to the Screening Visit. 
7. 
Positive test results for HIV-1/HIV-2 antibodies, HBsAg or Hepatitis C antibodies at 
the Screening Visit. 
8. 
Have a blood pressure reading outside of the following range: Systolic <86 or 
>149 mmHg; Diastolic <50 or >94 mmHg at the Screening Visit. 
9. 
Serious cardiac illness or other medical condition including, but not limited to: 
 
Uncontrolled arrhythmias 


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History of congestive heart failure  
 
QTcF >450 msec or history of prolonged QT syndrome  
 
Myocardial infarction  
 
Uncontrolled symptomatic angina 
10. 
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. 
11. 
Healthy participants who are taking, or have taken, any prescribed or 
over-the-counter drugs (other than 2 grams of acetaminophen per 24-hour period as 
of Day 1 or thyroid hormone replacement therapy [see Section 6.9]) or herbal 
remedies in the 14 days or 5 half-lives (whichever is longer) prior to dosing of study 
drug.  
12. 
Treatment with any known drugs that are moderate or strong inhibitors/inducers of 
CYP3A4 or CYP2C19, including St. John’s Wort, within 30 days prior to dosing of 
study drug. 
13. 
Any consumption of food or drink containing poppy seeds, grapefruit or Seville 
oranges within 14 days prior to dosing of study drug. 
14. 
Regular alcohol consumption >21 units per week (1 unit = ½ pint beer, 25 mL of 40% 
spirit or a 125 mL glass of wine). 
15. 
Positive test result for alcohol and/or drugs of abuse at the Screening Visit or at 
check-in. 
16. 
Concurrent treatment or treatment with an investigational drug or device within 
30 days or 5 half-lives (whichever is longer) prior to dosing of study drug. 
17. 
Blood donation of approximately 500 mL or more within 56 days or plasma donation 
within 7 days prior to the Screening Visit. 
18. 
Known hypersensitivity to INDV-2000. 
19. 
Has less than 1 bowel movement every 2 days. 
20. 
Recent history of abnormal bowel movements, such as diarrhea, loose stools or 
constipation, within 2 weeks prior to dosing of study drug. 
21. 
Has received radiolabelled substances or has been exposed to radiation sources over 
the past 12 months or is likely to receive radiation exposure or radioisotopes within 
the next 12 months such that participation in this study would increase their total 
exposure beyond the recommended levels considered safe (ie, weighted annual 
limit recommended by the FDA 21CFR361 of 3000 mrem; FDA 2023). 
22. 
Site staff and/or participants who have a financial interest in, or an immediate family 
member of either the site staff and/or Indivior employees, directly involved in the 
study. 


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23. 
Major surgical procedure (as defined by the Investigator) within 90 days prior to 
dosing of study drug or still recovering from prior surgery. 
24. 
Concurrent enrolment in another clinical study, unless it is an observational study. 
25. 
Participants who are unable, in the opinion of the Investigator, to comply fully with 
the study requirements. 
26. 
Any condition that, in the opinion of the Investigator or Indivior, would interfere 
with evaluation of the study drug or interpretation of participant safety or study 
results. 
5.3 Lifestyle Considerations 
5.3.1 Meals and Dietary Restrictions 
1. 
No water (except water provided with dosing) is allowed from 1 hour prior to and 
until 1 hour after dosing of study drug, but will be allowed ad libitum at all other 
times. 
2. 
On Day 1, participants will fast overnight for at least 10 hours before and at least 
4 hours after dosing of study drug.  
3. 
On all days that participants are confined in the study site, meals and/or snacks will 
be provided at appropriate times. Each meal and/or snack served at the study site 
will be standardised and will be similar in caloric content and composition. 
Participants will not be required to fully consume any meal or snack. 
4. 
Refrain from consumption of food or drink containing poppy seeds, grapefruit or 
Seville oranges from 14 days before dosing of study drug until after collection of the 
final PK sample. 
5. 
Participants should be instructed to fast for at least 12 hours before collection of 
fasting clinical laboratory assessment samples as indicated in Section 10.2 
(Appendix 2). 
5.3.2 Caffeine, Alcohol, and Tobacco 
1. 
Participants will be instructed to abstain from ingesting caffeine- or xanthine-
containing products (eg, coffee, tea, cola drinks, chocolate) for 24 hours prior to 
dosing of study drug until after collection of the final PK sample.  
Small amounts of caffeine derived from normal foodstuffs (eg, 250 mL/8 oz/1 cup 
decaffeinated coffee or other decaffeinated beverage, per day, with the exception of 
espresso; 45 g/1.5 oz chocolate bar per day) would not be considered a deviation to 
this restriction. 
2. 
Participants will be instructed to abstain from alcohol for 48 hours prior to dosing of 
study drug until after collection of the final PK sample. 
3. 
Participant will abstain from use of nicotine- or tobacco-products from 3 months 
before dosing of study drug and through confinement. 


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5.3.3 Activity 
1. 
Participants will remain seated for the first 4 hours post-dose, except when they are 
supine or semi reclined for study procedures. During the first 4 hours post-dose, 
participants may be allowed to rise for brief periods under supervision (eg, in order 
to use the toilet facilities). Participants will then resume normal activity.  
2. 
Specific measures will be taken to prevent the participant from missing a urine 
collection by strictly controlling and providing access to designated restrooms only. 
Participants will be asked to void prior to entering the shower. 
3. 
Should AEs occur at any time, participants may be placed in an appropriate position 
or will be permitted to lie down on their right side.  
4. 
Participants will be instructed to refrain from strenuous physical activity which could 
cause muscle aches or injury, including contact sports at any time from the 
Screening Visit until completion of the study. 
5.4 Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical study 
is not subsequently entered in the study. A minimal set of information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details (eg, reason for screen failure, 
such as not eligible, withdrew consent, AE), eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a 
reason that is expected to resolve or has resolved, may be rescreened based on discussion and 
agreement between the Investigator and the medical monitor. 
5.5 Enrolled Participant 
A participant will be considered enrolled if they are not a screen failure and received the study 
drug.  
5.6 Early Discontinuation  
A participant will be considered an early discontinuer if the participant received study drug and 
did not complete all visits or did not complete discharge criteria. Reasons for not completing all 
visits will be captured in the participant source documents and CRF.  
The definition of a study completer is provided in Section 4.4.  


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6 STUDY DRUG AND CONCOMITANT THERAPY 
Study drug is defined as any investigational drug(s), marketed product(s), placebo or medical 
device(s) intended to be administered to a study participant according to the study protocol. 
IDV184001AN and [14C]-IDV184001AN will be provided by Indivior 
 
 
6.1 Study Drug(s) Administered 
Table 2 
Study Drug Administered 
The study drugs’ labels will be developed in accordance with SOP and local regulatory 
requirements and approved by Indivior. 


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6.2 Preparation, Handling, Storage, and Accountability 
1. 
The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for IDV184001AN and [14C]-IDV184001AN received 
and any discrepancies are reported and resolved before use of the material as per 
the pharmacy manual. 
2. 
Only participants enrolled in the study may receive study drug and only authorised 
site staff may supply or administer study drug. The dispensing of study drug to the 
participant must be documented on the drug dispensing form. All study drug 
dispensation will be performed by a pharmacist or designee, checked by a study 
centre staff member and documented on a drug dispensation form. Refer to the 
pharmacy manual for further details. 
3. 
IDV184001AN, [14C]-IDV184001AN and study drug must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the 
Investigator and authorised site staff. 
4. 
The Investigator, institution, or the head of the medical institution (where 
applicable) is responsible for IDV184001AN, [14C]-IDV184001AN and study drug 
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, 
and final disposition records). 
5. 
Participant level dispensation of study drug must be documented on the appropriate 
participant 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.  
6. 
Used and unused IDV184001AN, [14C]-IDV184001AN and study drug must be 
available for verification by the site monitor during on-site monitoring visits.  
7. 
Further guidance and information for the final disposition of unused IDV184001AN, 
[14C]-IDV184001AN and study drugs are provided in the pharmacy manual. 
8. 
Upon completion of the study and/or as requested by Indivior, copies of 
IDV184001AN, [14C]-IDV184001AN and study drug accountability records will be 
provided to Indivior or designee. 
6.2.1 Drug Administration 
Participants will receive the study drug directly from the Investigator or designee, under 
medical supervision. 
A record of the amount of study drug dispensed to and taken by each participant must be 
maintained and reconciled with study drug and compliance records. Study drug administration 
date and time will be recorded in the CRF (See Section 6.5). 
Treatment is as follows: 
o 200 mg (~100 µCi) [14C]-IDV184001AN 
 on Day 1  


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 The pharmacy at the study site will provide each dose in individual unit dose containers 
for each participant, as appropriate. When the individual dose for a participant is 
prepared from a bulk supply, the preparation of the dose will be confirmed by a second 
member of the study-site staff. 
 Study drugs will be administered under fasted conditions with approximately 240 mL of 
water (see Section 5.3.1) as described in the pharmacy manual. 
 The exact clock time of dosing will be recorded. 
 Dosing compliance will be monitored as described in Section 6.5. 
6.2.2 Reporting Product Complaints 
The Investigator and study-site staff are responsible for prompt recognition and reporting of 
product quality complaints to Indivior 
 within 1 business day of 
identifying the issue.  
A product complaint is any concern pertaining to the manufacturing or quality control of 
IDV184001AN, [14C]-IDV184001AN or study drug and includes, but is not limited to: labelling 
defects, packaging defects, or material or study drug that is thought to be ineffective, or has an 
appearance, taste, or odour that is outside of what is expected. See the pharmacy manual for 
further details.  
The following information should be provided: 
 study number 
 site contact/reported by 
 participant number (if already assigned to a participant) 
 description of issue 
 picture, if available (photographs should be taken only if safe to do so/within site policy or 
practice to take photograph) 
Retain the product and packaging in quarantine for further investigation, as required. 
6.3 Assignment to Study Intervention 
The Investigator is responsible for maintaining a master list (ie, a participant identification list) 
of all consented participants and will document all participants that did not meet study 
eligibility criteria (ie, screen failures), including reason(s) for ineligibility (ie, a participant 
screening and enrolment log). 
Each participant will be assigned a unique identification number upon the Screening Visit. 
Participants who complete the study screening assessments and meet all the eligibility criteria 
will be assigned a unique identification number at the time of dosing, different from the 
screening number, and will receive the corresponding product.  
6.4 Blinding/Masking 
This is an open label, single treatment arm study. There is no randomisation in this study. 


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6.5 Study Drug Compliance 
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. The date and time of each dose administered will be recorded in the source documents 
and recorded in the CRF. A mouth check will be performed by the qualified designee to ensure 
that the participants have swallowed the study drug. Once a participant has finished the dosing 
water, the qualified designee will use a flashlight and a tongue depressor to check the 
participant’s mouth.  
Any deviation(s) from the prescribed dosage regimen will be recorded in the CRF. 
The time of dosing is defined as the time the participant has swallowed the study drug and the 
qualified designee has completed check of oral cavity. 
The exact clock time of dosing will be recorded. 
6.6 Dose Modification 
The dose and administration of the study drug to any participant may not be modified. 
6.7 Treatment Access to Study Drug After the End of the Study 
Not applicable. 
6.8 Treatment of Study Drug Overdose 
For this study, any dose of study drug greater than that specified in the protocol will be 
considered an overdose. In the event of overdose, general supportive measures and close 
monitoring are recommended.  
Overdoses are medication errors that are not considered AEs unless there is an untoward 
medical occurrence resulting from the overdose. 
In the event of an overdose, the Investigator should do the following: 
1. Evaluate the participant to determine, in consultation with the medical monitor, if 
possible, whether study drug should be interrupted or whether the dose should be 
reduced. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Obtain a plasma sample (for IDV184001) for PK analysis within 24 hours from the time 
of dosing of study drug if requested by the medical monitor (determined on a case-by-
case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose. 
6.9 Prior and Concomitant Therapy 
Any medication (including prescription and non prescription medications, vitamins and dietary 
or herbal supplements) that the participant is receiving during the study must be recorded 
along with the following: 
• Reason for use 
• Dates of administration including start and end dates 


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• Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must not have received concurrent treatment or treatment with an investigational 
drug or device within 5 half-lives (if known) of the investigational agent or 30 days prior to 
dosing of study drug, whichever is longer. 
Participants must abstain from taking any prescribed or over-the-counter drugs or herbal 
remedies within 14 days or 5 half-lives (whichever is longer) prior to dosing of study drug until 
study discharge. Thyroid hormone replacement therapy, if the participant has been on the 
same stable dose for at least 3 months prior to dosing, will be allowed. After dosing of study 
drug, acetaminophen, at doses of up to 2 g/24 hours, is permitted for use at the discretion of 
the Investigator or designee. Milk of Magnesia (ie, magnesium hydroxide) (≤60 mL per day) or 
prune juice may be administered from 24 hours after dosing at the discretion of the 
Investigator or designee. 
Moderate or strong inhibitors/inducers of CYP3A4 or CYP2C19, including St. John’s Wort, will be 
prohibited within 30 days prior to dosing of study drug until study discharge. Appropriate 
sources (eg, Flockhart Table™) will be consulted to confirm lack of PK/pharmacodynamic 
interaction with the study drug. 
 
 


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7 DISCONTINUATION/WITHDRAWAL AND STOPPING CRITERIA 
7.1 
Discontinuation from Study and Study Stopping Criteria 
In rare instances, it may be necessary for a participant to permanently withdraw from study. 
See the SoE (Section 1.3) for data to be collected at the time of discontinuation of study and for 
any further evaluations that need to be completed. 
7.2 Participant Discontinuation/Withdrawal From the Study 
• A participant may withdraw from the study at any time at the participant’s own request 
for any reason (with or without providing any reason). 
• A participant may be withdrawn at any time at the discretion of the Investigator for 
safety, behavioural or compliance reasons. 
• At the time of discontinuing from the study, if possible, discharge assessments should 
be conducted, as shown in the SoE (Section 1.3).  
• Participants who terminate the study early will be asked to return to the study site 
7±2 days after dosing for follow-up procedures, and to determine if any AE has occurred 
since the last study visit, as shown in the SoE (Section 1.3). 
• The participant will be permanently discontinued both from the study drug and from 
the study at that time. 
• The participant will be encouraged to stay up to 24 hours post-dose to complete 
discharge assessments.  
• If the participant withdraws consent for disclosure of future information, Indivior may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, the participant may request destruction of 
any samples taken and not tested, and the Investigator must document this in the site 
study records. 
Should any participant withdraw or be withdrawn from the study, they will be cautioned 
against activities requiring mental alertness, judgment and physical coordination such as 
driving, operating machinery, or power equipment for a period of 24 hours post-dose. 
7.3 Lost to Follow-up 
An enrolled participant who has received study drug will be considered lost to follow-up if he 
repeatedly fails to return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study. 


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• Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant [where possible, 2 contact 
attempts (eg, telephone calls and/or emails and, if necessary a certified letter to the 
participant’s last known mailing address or local equivalent methods)]. These contact 
attempts should be documented in the participant’s medical record.  
• Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study and the date of withdrawal is the last contact.  
 
 


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8 STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarised in the SoE (Section 1.3); individual 
clinical procedures are described in detail below. 
• Adherence to the study design requirements, including those specified in the SoE, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• For this study, the blood collection for PK assessments of unlabelled IDV184001 and 
M12 (plasma), blood (whole blood and plasma), urine, and feces collection for TRA, and 
blood (plasma), urine, and feces for the metabolic profiling are the critical parameters 
and need to be collected as close to the exact time point as possible. All other 
procedures should be completed as close to the prescribed/scheduled time as possible, 
but can be performed prior to or after the prescribed/scheduled time. Any non-
scheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
• Repeat or unscheduled samples may be obtained for safety reasons. 
• In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution, and monitoring 
may be implemented by Indivior or the Investigator, as per local health authority/ethics 
requirements.  
Table 3 
Blood Volume during the Study 


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8.1 Administrative Procedures 
8.1.1 Informed Consent Procedure 
Refer to Section 10.1.3. 
8.1.2 Inclusion and Exclusion Criteria 
Refer to Section 5.1 and Section 5.2. 
8.1.3 Medical History/Demography 
At screening, medical history and demographic data, including name, sex, age, race, 
ethnicity, psychiatric history, and substance use will be recorded.  
8.1.4 Concomitant Medications 
Concomitant medications will be prohibited as listed in Section 6.9. All medications 
taken by participants during the course of the study will be recorded. 
8.1.5 Check-in Criteria 
Upon passing screening and meeting inclusion and not meeting exclusion criteria, the 
participant will be admitted to the study site on Day -1. Once admitted, participants 
must meet the following criteria prior to Day 1 dosing: 
• A check-in questionnaire will be reviewed for each participant to ensure that 
participants remain eligible for the study since screening. Questions will focus on 
inclusion and exclusion criteria and on study restrictions.  
• Participants must have a negative result obtained from the urine drug screen and 
the alcohol test. 
o Healthy participants 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. 
• Participants must have a negative rapid test result for COVID-19. 
• Meets ECG entry criteria. 
If any of these criteria are not met, the participant will not be enrolled. 
8.2 Efficacy and/or Immunogenicity Assessments 
Efficacy and/or immunogenicity are not evaluated in this study. 
8.3 Safety Assessments 
Planned time points for all safety assessments are provided in the SoE (Section 1.3). Individual 
clinical procedures are described in detail below. 
Additional safety assessments may be performed at various unscheduled time points, if 
deemed necessary by the Investigator or designee. 


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8.3.1 Physical Examinations 
• Physical examination will be conducted as outlined in the SoE (Section 1.3). 
• Additional physical examinations may be performed at other times, if deemed necessary 
by the Investigator or designee. 
• A complete physical examination will include, at a minimum, an examination of all major 
body/organ systems (including skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, 
heart, abdomen, lymph nodes, and extremities). Height and weight (with participants 
wearing indoor, daytime clothing with no shoes) will also be measured and recorded as 
outlined in the SoE (Section 1.3). 
8.3.2 Vital Signs 
• Single vital signs will include the collection of oral body temperature, respiratory rate, 
blood pressure, and pulse rate and will be conducted as outlined in the SoE 
(Section 1.3). 
• Blood pressure and pulse rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• Blood pressure and pulse rate will be assessed with the participant resting in a seated 
position for at least 5 minutes, except when participants are supine or semi-reclined 
because of study procedures and/or AEs (eg, nausea, dizziness) or if deemed necessary 
by the Investigator or designee. 
• When scheduled pre-dose, vital signs will be measured within 2 hours prior to dosing for 
the pre-dose time points. When scheduled post-dose, vital signs will be performed 
within approximately 15 minutes of the scheduled time point. 
8.3.3 Electrocardiograms 
• Single 12-lead ECG will be conducted as outlined in the SoE (Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTcF intervals. 
• ECGs will be performed with participants resting in a supine position for at least 
5 minutes. All ECG tracings will be reviewed by the Investigator or designee. 
• When scheduled pre-dose, ECGs will be measured within 2 hours prior to dosing. When 
scheduled post-dose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point. 
8.3.4 Clinical Safety Laboratory Tests 
• See Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed and 
to the SoE (Section 1.3) for the timing and frequency. 


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• The Investigator must review the laboratory results, document this review and record 
any clinically relevant changes occurring during the study as an AE. The laboratory 
results must be retained with the source documents.  
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the Investigator or medical 
monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and Indivior 
notified. 
o All protocol-required laboratory tests, as defined in Section 10.2 (Appendix 2), must 
be conducted in accordance with the laboratory manual and the SoE (Section 1.3). 
o If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded. 
o Serum chemistry tests will be performed after at least an 12-hour fast; however, in 
case of dropouts or rechecks, participants may not have fasted for 12 hours prior to 
when the serum chemistry sample is taken.  


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8.4 Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs are provided below, as are criteria for assessment of AE/SAE 
intensity and causality.  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures or that 
caused the participant to withdraw from the study (see Section 7). 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study drug, whether or not considered related to 
the study drug. 
• NOTE: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study drug. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (haematology, clinical chemistry, coagulation, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from screening (signing of the ICF), 
considered clinically significant in the medical and scientific judgement of the 
Investigator (ie, not related to progression of underlying disease, or more severe than 
expected for the participant’s condition). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study drug administration even though it 
may have been present before signing the ICF. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction or that 
resulted in additional intervention (eg, concomitant medication, surgery). 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless 
it is an intentional overdose taken with possible suicidal/self-harming intent. Such 
overdoses should be reported regardless of sequelae. 
Events not meeting the AE definition 
• Any abnormal laboratory findings or other abnormal safety findings that are not 
considered to be clinically significant by the Investigator. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, hospitalisation for elective surgery, hospitalisation 
for observation in the absence of an AE). 


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Definition of SAE 
An SAE is defined as any untoward medical occurrence that: 
a. Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• In general, hospitalisation signifies that the participant requires inpatient 
HOSPITALISATION or prolongation of existing hospitalisation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from screening (signing of the ICF) is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Medical or scientific judgement should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
o Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of study drug 
dependency or study drug abuse. 
 An SAE must be reported for participants with ALT or AST ≥3 × ULN and bilirubin 
≥2 × ULN (>35% direct). 


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Definition of SUSAR 
A SUSAR is an SAE with at least a reasonable possibility of being related to the study drug 
(ie, the relationship cannot be ruled out), the nature or severity of which is not consistent 
with the applicable product information (eg, IB for an unapproved investigational product 
or package insert/summary of product characteristics for an approved product). 
Assessment of Intensity 
The Investigator will assess intensity for each AE and SAE reported during the study and assign 
it to 1 of the following categories:  
• Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
• Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
Assessment of Toxicitiy  
Separately, the toxicity of AEs 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 10.5). Any event not falling under one of the specific categories 
listed will be graded as a “Systemic Illness”. 
For events that occur after signing of the ICF, the maximum intensity, toxicity, and seriousness 
should be reflected in the event record. 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. The relationship of each AE to study drug will be assessed 
using the following categories: 
o Related: An AE that follows a reasonable temporal sequence from administration of 
a drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be ruled 
out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible. 
o Not Related: An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by other factors, 
such as underlying diseases, complications, concomitant medications and 
concurrent treatments.  


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• The Investigator will use clinical judgement to determine the relationship.  
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drug administration 
will be considered and investigated. 
• For causality assessment, the Investigator will also consult the IB and/or product 
information, for marketed products. 
• The Investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes. There may be situations in which an SAE has 
occurred and the Investigator has minimal information to include in the initial report to 
Indivior. However, it is very important that the Investigator always make an assessment 
of causality for every event before the initial transmission of the SAE data to Indivior. 
• The Investigator may change opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Clinical Laboratory Changes 
Changes in laboratory values, vital signs, or other safety parameters (eg, neurological and 
clinical symptom assessments) as noted in the protocol are a subset of AEs and are reportable 
only if the laboratory 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. 
8.4.1 Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from ICF signature until discharge on Day 8 (up to Day 22). 
Any ongoing AEs at the time of discharge will be appropriately followed-up until resolution or 
14 days (±2 days) after discharge or early termination. Any ongoing SAEs will be followed-up 
until resolution or lost to follow-up. 
All SAEs will be recorded and reported to Indivior or designee immediately and under no 
circumstance should this exceed 24 hours from first becoming aware of the event, as indicated 
in Section 8.4.3. The Investigator will submit any updated SAE data to Indivior within 24 hours 
of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and the Investigator considers the event to 
be reasonably related to the study drug or study participation, the Investigator must promptly 
notify Indivior. 


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8.4.2 Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3 Reporting and Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilisation, 
the event is otherwise explained or the participant is lost to follow up (as defined in 
Section 7.3). Further information on follow up procedures is provided in Section 8.4.3.2. 
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 8.4.  
8.4.3.1 Reporting of SAEs 
SAE Reporting to Indivior via Paper SAE Reporting Form 
• The primary mechanism for reporting an SAE to Indivior Pharmacovigilance will be by 
completing the Paper SAE Reporting Form provided by Indivior. Follow-up information 
will also be reported using the paper SAE Reporting Form. 
o The SAE Reporting Form should be completed and submitted to Indivior 
Pharmacovigilance: 
 
 
• The site will report all SAEs within 24 hours from first being aware of the event. Any 
follow-up information on a previously reported SAE will also be reported to Indivior 
within 24 hours. 
8.4.3.2 Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF.  
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Indivior in lieu of completion of the required form. 


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• There may be instances when copies of medical records for certain cases are requested 
by Indivior Pharmacovigilance. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records before 
submission to Indivior Pharmacovigilance. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Indivior 
Pharmacovigilance to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to Indivior within 24 hours of receipt 
of the information. 
• After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilisation, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). 
8.4.4 Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to Indivior of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study drug under clinical investigation are met. 
• Indivior has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. Indivior 
will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from Indivior will review and 
then file it along with the IB and/or package insert and will notify the IRB/IEC, if 
appropriate according to local requirements. 
• Investigator safety reports must be prepared for SUSAR according to local regulatory 
requirements and Indivior policy and forwarded to Investigators as necessary. 
8.4.5 Pregnancy 
• Details of all pregnancies in female partners of male participants will be collected after 
study drug administration and until 90 days following dosing.  


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• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to Indivior within 24 hours of learning of the female 
partners of male participants (after obtaining the necessary signed informed consent 
from the female partner) pregnancy.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE. 
• All pregnancy exposure cases (unless permission has been denied), where the embryo 
or foetus may have been exposed to study drug (ie,  through transmission of a medicinal 
product via semen following paternal exposure) whether associated with an AE or not, 
will be followed in order to collect information on the outcome of the pregnancy (ie, 
termination [voluntary or spontaneous] or birth). Make 2 attempts to obtain 
information after the expected due date, with 1 month between the 2 attempts. If there 
is no response, the case will be closed. 
• Abnormal pregnancy outcomes (eg, foetal death, stillbirth, congenital anomalies, 
ectopic pregnancy, abortion [except pregnancy in habitual aborter, prophylaxis of 
abortion], pre-eclampsia, eclampsia) are considered SAEs and will be reported as such. 
• The female partners of male participants will be followed to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on the female 
partners of male participants and the neonate and the information will be forwarded to 
Indivior. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study drug 
by the Investigator will be reported to Indivior as described in Section 8.4.4. While the 
Investigator is not obligated to actively seek this information in female partners of 
former male participants, he or she may learn of an SAE through spontaneous reporting. 
8.5 Pharmacokinetics 
• Blood samples will be collected for measurement of plasma concentrations of 
unlabelled IDV184001 and M12, TRA measurement in plasma and whole blood, and 
plasma metabolic profiling as specified in Section 10.4 (Appendix 4). 
• The allowable deviation window for PK blood sample collection is detailed Section 10.4 
(Appendix 4).  
• Instructions for the collection and handling of biological samples will be provided in the 
Laboratory Manual. The actual date and time (24-hour clock time) of each sample will 
be recorded.  
• Pre-dose samples should be handled, processed, analysed, and stored separately away 
from the post-dose samples to avoid cross contamination. 
• For urine collection, each participant will be instructed as to urine collection methods 
prior to collection of the pre-dose sample. All urine during an interval is to be collected. 
On Day 1, a spot collection will be obtained prior to dosing for the pre-dose sample. 


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Participants will be asked again to empty their bladder within approximately 15 minutes 
prior to dosing, and no urine will be collected at this time unless it is needed for the 
pre-dose sample. Only one pre-dose urine sample will be collected on Day 1. Participants 
will be encouraged to void at the end of each collection interval. If they do void at any 
time during the collection interval, the time should be documented. Should this be the 
case, participants need to void again at the end of the collection period, as scheduled. 
However, should participants be unable to void, this will be documented as well.  
• Urine will be refrigerated during the collection intervals. At the end of each interval, 
urine will be pooled and thoroughly mixed. Total urine volume will be weighed and 
recorded. 
• For feces collection, the pre-dose fecal sample will be obtained within 48 hours prior to 
dosing. Participants will be asked to bring a fecal sample at check-in (if produced within 
48 hours prior to dosing). Feces produced between check-in and dosing will also be 
collected as a pre-dose sample with the sample produced nearest to dosing to be 
retained as the only pre-dose sample. 
• All fecal samples will be collected and stored individually for analysis of PK assessments. 
Multiple fecal samples from a given participant in a given interval will be pooled into a 
single sample at the time of homogenization. 
• Collection containers (pre-weighed) for emesis will be available for participants 
participating in the study at all times following dosing. Participants will be instructed at 
the beginning of the study that they should use one of the designated containers if 
emesis occurs at any time throughout the study following dosing. If emesis is collected 
in the designated container, it will be weighed and recorded, labelled with participant 
identification, time, and date, and analysed for TRA. 
• Samples from all participants will be assayed even if the participants do not complete 
the study. Samples will be analysed using validated bioanalytical methods.  
• No additional analysis is planned to be performed on the PK samples for possible future 
research. Any additional research on these samples unspecified by this protocol will 
require approval from the participants. 
8.6 Pharmacodynamics 
Pharmacodynamics are not evaluated in this study. 
8.7 Genetics 
Genetics are not evaluated in this study. 
8.8 Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 Medical Resource Utilisation and Health Economics 
Medical resource utilisation and health economics parameters are not evaluated in this study. 


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9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
There are no formal statistical hypotheses for this study.  
9.1.1 Multiplicity Adjustment 
There are no inferential statistics for this study; therefore, multiplicity adjustment is not 
applicable.  
9.2 Analyses Sets 
For purposes of analysis, the following populations are defined: 
Table 4 
Populations for Analysis 
Population 
Description 
Screened 
All participants who sign the ICF. 
PK Analysis Set 
All participants who receive the study drug and have an adequate 
number of PK samples collected to derive any ADME parameter, and 
have no protocol deviations that would significantly alter 
concentrations of study drug. All available data will be included in the 
concentration and ADME parameter tables to the extent possible.  
Safety Analysis Set 
All participants who receive the study drug.  
9.3 Statistical Analyses 
9.3.1 General Considerations 
The SAP will be finalised prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and secondary 
endpoints. 
9.3.2 Primary Endpoints Analysis 
Primary endpoints analysis will be based on a sample collection timeframe from pre-dose to 
168 hours post-dose or longer as applicable. Primary endpoints will be summarised for the PK 
Analysis Set. 
9.3.2.1 Mass Balance 
Total radioactivity recovery and the percent of the radioactive dose excreted in the urine and 
feces from pre-dose to at least 168 hours, as applicable, will be assessed on a per participant 
basis. Mass balance will be calculated as a sum of the percent of the TRA recovered in urine and 
feces relative to the administered radioactive dose. If emesis occurs, the calculation of mass 
balance may take into account any radioactivity recovered in the vomitus as appropriate. 


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9.3.2.2 PK Analysis 
Values will be calculated for TRA concentration equivalents, unlabelled IDV184001 and M12 
concentration equivalents from pre-dose to at least 168 hours, as applicable, and for PK 
parameters (listed below) using appropriate summary statistics to be fully described in the SAP.  
 TRA PK parameters in plasma and whole blood: AUClast, AUC0-∞, AUCextrap(%), Cmax, Tmax, λz 
and T1/2. 
 TRA PK parameters in urine and feces: Aet1-t2, CumAe, %Dose, Cum%Dose, and CLr (urine 
only). 
 Unlabelled IDV184001 and M12 PK parameters in plasma: AUClast, AUC0-∞, AUCextrap(%), 
Cmax, Tmax, λz, T1/2. 
 Ratio of unlabelled IDV184001 and M12 in plasma to plasma TRA for AUClast and Cmax, 
where appropriate. 
9.3.2.3 Metabolite Identification, Profiling and Quantitation 
IDV184001 metabolite identification, profiling and quantitation will be performed on plasma, 
urine, and fecal samples from pre-dose to at least 168 hours, as applicable, containing sufficient 
amounts of radioactivity. The percent of dose in urine and feces and % of AUC in plasma 
represented by each of the metabolites, if any, will be calculated using the radioactive 
concentration equivalent data combined with the metabolite identification, profiling and 
quantitation data. The percentage of each identified metabolite, if any, to TRA in the plasma, 
urine, and feces will be estimated based on plasma, urine, and feces metabolite identification, 
profiling and quantitation data. 
9.3.2.4 Whole Blood to Plasma Partitioning Ratio 
The ratio of TRA concentration equivalents in whole blood relative to plasma at each time 
matched determination of TRA in whole blood and plasma from pre-dose to at least 168 hours, 
as applicable, will be calculated. 
9.3.3 Secondary Endpoints Analysis 
TEAEs will be defined as AEs that start at or after dosing of study drug and will be summarised 
by Medical Dictionary for Regulatory Activities system organ class and preferred term. TEAEs 
will be summarised for the Safety Analysis Set.  
9.3.4 Tertiary Endpoints Analysis 
9.4 Interim Analysis 
No interim analysis is planned. 


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9.5 Sample Size Determination 
Approximately 7 participants will be assigned to receive study drug. According to the FDA 
Guidance for Industry: Clinical Pharmacology Considerations for Human Radiolabelled Mass 
Balance Studies (FDA 2022), a sample size of at least 6 participants is required to meet the 
study objectives. Thus, 7 healthy male participants will be dosed to account for at most 1 
possible dropout. This sample size is limited based on clinical considerations for this type of 
study and in order to limit exposure to radioactivity. 
 
 
 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
o Applicable ICH GCP guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before use in the study. If required by local regulations, the 
protocol should be re-approved by the IRB/IEC annually. The IRB/IEC must be 
constituted and operate in accordance with the principles and requirements of ICH/GCP.  
• Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• Protocols and any substantial amendments to the protocol may require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following, as applicable: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations 
10.1.2 Financial Disclosure 
Investigators and subinvestigators will provide Indivior with sufficient, accurate financial 
information (when applicable) as requested to allow Indivior to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course 
of the study and for 1 year after completion of the study. 


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10.1.3 Informed Consent Process 
• The Investigator or the Investigator’s representative will explain the nature of the study 
to the participant and answer all questions regarding the study. 
• Potential participants must be informed that their participation is voluntary. They will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, and privacy and data protection 
requirements, where applicable, and the IRB/IEC or study centre. 
• Written informed consent must be obtained prior to any study-related.  
• The authorised person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study, if required by the IRB/IEC. 
• A copy of the ICF(s) must be provided to the participant. 
10.1.4 Data Protection 
• Participants will be assigned a unique identifier by the study site. Any participant 
records or datasets that are transferred to Indivior will contain the identifier only; 
participant names or any information which would make the participant identifiable will 
not be transferred. 
• Participants must be informed that their personal study-related data will be used by 
Indivior in accordance with local data protection law. The level of disclosure must also 
be explained to the participant who will be required to give consent for their data to be 
used as described in the informed consent.  
• Participants must be informed that their study records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by Indivior, and by 
inspectors from regulatory authorities. 
• The contract between Indivior and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data 
are secured by technical and organisational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorised disclosure or access. 
10.1.5 Dissemination of Clinical Study Data 
This study will be registered on ClinicalTrials.gov, European Clinical Trials Database, or the 
country’s clinical study registry, as appropriate, and in accordance with national, regional, and 
local regulations. Release of applicable clinical study results will proceed in compliance with 
local regulations in accordance with the principles of Good Publication Practice. 
A clinical study report will be prepared following completion of the study. An Investigator 
signatory may be identified for the approval of the report if required by applicable regulatory 
requirements. 


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10.1.6 Data Quality Assurance 
• Data will be collected directly or transcribed from original sources by the Investigator or 
designee into the databases used for CRF generation. The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing 
the CRF. 
• Guidance on completion of CRFs will be described in the CRF completion guidelines. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections, and provide direct access to source data documents. 
• Investigator Site Audits include, but are not limited to, review of drug supply, presence 
of required documents, the informed consent process, comparison of CRFs with source 
documents, and any other study-specific information/documentation that the auditor 
deems appropriate for review during the audit. The Investigator agrees to participate 
with audits conducted at a reasonable time in a reasonable manner. Full consultation 
with the Investigator will be made prior to and during such an audit, which will be 
conducted according to Indivior’s or a Contract Research Organization’s Quality 
Assurance SOPs.  
• In addition, this study is subject to inspections by regulatory authorities. If such a 
regulatory inspection occurs, the Investigator agrees to allow the regulatory inspector 
direct access to all relevant study documents. The Investigator must contact Indivior 
immediately if this occurs and must fully cooperate with the inspection conducted at a 
reasonable time in a reasonable manner. 
• Monitoring details describing strategy including definition of study critical data items 
and processes (eg, risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities and requirements, including handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
monitoring plan. 
• Indivior or designee is responsible for the data management of this study including 
quality checking of the data. 
• Indivior assumes accountability for actions delegated to other individuals (eg, contract 
research organisations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator as dictated by ICH/GCP guidelines, as well as in 
accordance with the site’s Standard Operating Procedure requirements and local 
regulations or institutional policies. No records may be destroyed without the written 
approval of Indivior. No records may be transferred to another location or party without 
written notification to Indivior. 


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10.1.7 Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
• The Investigator is responsible for the quality of the data recorded in the CRFs. The data 
recorded should be a complete and accurate account of the participant’s record 
collected during the study. 
• Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained. The Investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.  
• 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. 
When using a direct entry CRF, the CRF will be considered the source document for 
applicable CRF elements collected directly onto a CRF. Source documents will include, 
but are not limited to, progress notes, electronic data, screening logs, and recorded data 
from automated instruments. 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 authorised study personnel 
outlined in the ICF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Indivior or designee will perform monitoring to confirm that data entered into the CRF 
by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.8 Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the time study is published to the call centre and 
Helpresearch.com website and will be the study start date. 
Study/Site Termination 
Indivior or designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of Indivior. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Indivior or Investigator may include but are not 
limited to the following: 
For study termination: 
• Discontinuation of further study drug development 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, Indivior procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, Indivior shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
10.1.9 Publication Policy 
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. 
 Indivior will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, Indivior will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 5 will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations.  
 
 


I N D V-2 0 0 0  
Cli nic al St u dy Pr ot oc ol: I N D V -2 0 0 0 -1 0 5 Fi n al  
I n di vi or 
1 5  M a y 2 0 2 3  
 
C o nfi d e nti al  
P a g e 6 1  of 7 8 
T a bl e 5 
Pr ot oc ol -r e q uir e d S af et y L a b or at or y Tests  
H a e m at ol o g y  
 
S er u m C h e mistr y *  
 
H a e m o gl o bi n  
 
H a e m at ocrit  
 
T ot al a n d diff er e nti al l e u k ocyt e c o u nt  
 
R e d bl o o d c ell c o u nt  
 
Pl at el et c o u nt  
 
C o a g ul ati o n 
 
Pr ot hr o m bi n ti m e/ I N R 
 
A ctiv at e d p arti al t hr o m b o pl asti n 
 
 
 
Bl o o d Ur e a Nitr o g e n  
 
Bilir u bi n (t ot al a n d dir ect)  
 
AL P 
 
A S T  
 
A L T 
 
G a m m a -gl ut a m yl  Tr a nsf er as e  
 
Al b u mi n  
 
S o di u m  
 
P ot assi u m  
 
C hl ori d e  
 
Gl uc os e (f asti n g)  
 
Cr e ati ni n e * *  
 
T ot al pr ot ei n  
 
T ot al c h ol est er ol  
 
Tri gl yc eri d es  
 
Cr e ati n e  p h os p h o ki n as e  
 
Uri n al ysis  
 
A d diti o n al T ests  
 
p H  
 
S p ecific gr a vit y  
 
Pr o t ei n * * * 
 
Gl uc os e  
 
K et o n es  
 
Bilir u bi n  
 
Bl o o d * * *  
 
Nitrit e * * *  
 
Ur o bili n o g e n  
 
L e u k ocyt e est er as e * * * 
 
 
HI V -1; HI V -2 (scr e e ni n g o nl y)  
 
H Bs A g (scr e e ni n g o nl y)  
 
H C V  a nti b o di es (scr e e ni n g o nl y) 
 
Uri n e dr u g scr e e n  
 
O pi at es  
 
O pi oi ds  
 
A m p h et a mi n es  
 
B ar bit ur at es  
 
B e nz o di az e pi n es  
 
C oc ai n e  
 
C a n n a bi n oi ds  
 
F e nt a n yl  
 
Ox yc o d o n e  
 
Uri n e alc o h ol scr e e n  
 
C O VI D - 1 9 r a pi d t est (c h ec k-i n o nl y) 
 
* 
S er u m c h e mistr y t ests will b e p erf or m e d aft er at l e ast a n 1 2- h o ur f ast; h o w e v er, i n c as e of dr o p o uts or r ec h ec ks, 
p artici p a nts  m a y n ot h a v e f ast e d f or 1 2 h o urs pri or t o w h e n t h e s er u m c h e mistr y s a m pl e is t a k e n . 
* *  At t h e S cr e e ni n g V isit, cr e ati ni n e cl e ar a nc e will b e c alc ul at e d usi n g t h e C oc kcr oft-G a ult f or m ul a . 
* * *  If uri n alysis is a b n or m al f or pr ot ei n, bl o o d, nitrit e a n d/ or l e u k ocyt e est er as e, a micr osc o pic ex a mi n ati o n (f or r e d bl o o d 
c ells, w hit e bl o o d c ells, b act eri a, c asts, a n d e pit h eli al c ells) will b e p erf or m e d. 
 


I N D V-2 0 0 0  
Cli nic al St u dy Pr ot oc ol: I N D V -2 0 0 0 -1 0 5 Fi n al  
I n di vi or 
1 5  M a y 2 0 2 3  
 
C o nfi d e nti al  
P a g e 6 2  of 7 8 
1 0. 3  A p p e n di x  3: C o ntr ac e pti v e G ui d a nc e a n d C oll ecti o n of Pr e g n a nc y I nf or m ati o n 
1 0. 3. 1  C o ntr ac e pti o n G ui d a nc e  
M al e P artici p a nts  
M al e p artici p a nts wit h f e m al e p art n ers of c hil d b e ari n g p ot e nti al m ust c o m pl y wit h t h e 
f oll o wi n g c o ntr ac e pti o n r e q uir e m e nts fr o m t h e ti m e of d osi n g  of st u d y dr u g u ntil at l e ast 
9 0  d a ys aft er d osi n g of st u d y dr u g .  
•  All n o n -st eril e m al e p artici p a nts m ust us e hi g hl y eff ecti v e c o ntr ac e pti o n fr o m st u d y dr u g 
a d mi nistr ati o n t hr o u g h 9 0 d a ys aft er st u d y dr u g a d mi nistr ati o n if s ex u all y acti v e wit h a 
n o n -pr e g n a nt p art n er of c hil d b e ari n g p ot e nti al. Hi g hl y eff ecti v e c o ntr ac e pti o n is 
d efi n e d as:  
o  
Tr u e s ex u al  a bsti n e nc e  
o  
C o n d o m pl us p art n er’s us e o n e of  t h e f oll o wi n g:  
 
Or al, i ntr a v a gi n al,  i nj ect a bl es, i m pl a nts, or tr a ns d er m al c o m bi n e d 
( estr o g e n- a n d pr o g est o g e n -c o nt ai ni n g) h or m o n al c o ntr ac e pti o n 
ass oci at e d wit h i n hi biti o n of ov ul ati o n  
 
I ntr a ut eri n e d e vic e  
 
I ntr a ut eri n e h or m o n e-r el e asi n g s yst e m  
 
Bil at er al t u b al occl usi o n  
•  N o r estricti o ns ar e r e q uir e d f or a v as ect o mi se d m al e pr ovi d e d his v as ect o m y h as b e e n 
p erf or m e d 4 m o nt hs or m or e pri or t o d osi n g. A m al e w h o h as b e e n v as ect o mi se d l ess 
t h a n 4 m o nt hs pri or t o d osi n g m ust f oll o w t h e s a m e r estricti o ns as a n o n-v as ect o mi s e d 
m al e.  
•  M al e p artici p a nt m ust a gr e e n ot t o d o n at e s p er m fr o m d osi n g u ntil at l e ast 9 0  d a ys 
p ost -d os e . 
 


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10.4 Appendix 4: Pharmacokinetic Sampling Schedule 
Table 6 
Blood PK sampling schedule 


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Table 7 
Urine sampling schedule 


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Table 8 
Fecal sampling schedule 


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Table 9 
List of Whole Blood and Plasma Pharmacokinetic Parameters (non-exhaustive) 
TRA, Unlabelled IDV184001 and M12 
Cmax 
Maximum observed concentration 
Tmax 
Time of maximum observed concentration 
AUClast 
Area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration; calculated using the linear trapezoidal rule 
AUC0-∞ 
Area under the concentration-time curve from time 0 extrapolated to infinite 
time 
AUCextrap(%) 
Percent of the area under the concentration-time curve due to extrapolation 
λz 
Terminal phase rate constant 
T1/2 
Apparent terminal half-life 
CL/F 
Apparent total clearance after oral (extravascular) administration, calculated 
as Dose/ AUC0-∞ (parent only) 
Vz/F 
Apparent volume of distribution during the terminal elimination phase after 
oral (extravascular) administration, calculated as Dose/(AUC0-∞xλz) (parent 
only) 
MRAUC0-∞ 
Metabolic ratio of the metabolite AUC0-∞ to the parent AUC0-∞ 
MRCmax 
Metabolic ratio of the metabolite Cmax to the parent Cmax 


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R AUClast (plasma) 
Ratio of unlabelled plasma study drug AUClast to plasma TRA AUClast 
R Cmax (plasma) 
Ratio of unlabelled plasma study drug Cmax to plasma TRA Cmax 
Analysis may include calculation of other PK parameters as applicable. PK calculations will be 
performed using WinNonlin Phoenix version 8.3.4 or higher (Pharsight Corporation). 
No value for AUC0-∞, λz, AUCextrap(%), CL/F, Vz/F, and T1/2 will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration-time profile. To the extent possible, 
AUC0-∞ values for all participants including the percentage of extrapolation will be reported.  
Handling of concentrations below the limit of quantitation will be addressed in the SAP for 
calculations of PK parameters and for summary statistics of plasma concentrations. 
Table 10 
List of Urine and Feces Pharmacokinetic Parameters (non-exhaustive) 
TRA 
Aet1-t2 
Amount of total radioactivity excreted/recovered within a given collection 
interval 
CumAe 
Cumulative amount of total radioactivity excreted/recovered 
%Dose 
Percent of administered dose excreted/recovered within a given collection 
interval 
Cum%Dose: 
Cumulative percent of dose excreted/recovered 
CLr 
Renal clearance. CLr = Aet1-t2/AUC, where both Aet1-t2 and AUC are determined 
over matched time interval (urine only) 
Analysis may include calculation of other PK parameters as applicable. PK calculations will be 
performed using SAS version 9.4 or higher. 
 
 
 


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10.5 Appendix 5: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 200 N, 
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. 
 
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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Guidance for Industry 
Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials 
 
I. 
Introduction 
Preventive vaccines are usually developed to prevent disease in a healthy population. The 
Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, regulates 
preventive vaccines under authority of section 351 of the Public Health Service Act 
(42 U.S.C.262), as well as specific sections of the Federal Food, Drug, and Cosmetic Act, and 
reviews investigational new drug applications (INDs) and biologics license applications (BLAs). 
(See, for example, Title 21 CFR Parts 312, 600, and 601). Most of the clinical trials of preventive 
vaccines conducted to support INDs and BLAs enroll healthy volunteers in all phases of vaccine 
testing. The enrolment of healthy volunteers warrants a very low tolerance for risk in those 
clinical trials. 
This guidance provides you, sponsors, monitors, and investigators of vaccine trials, with 
recommendations on assessing the severity of clinical and laboratory abnormalities in healthy 
adult and adolescent volunteers enrolled in clinical trials. The grading system described in the 
table can also be useful in defining a particular study’s stopping rules (eg, a certain number of 
adverse events, as defined in the table, may call for stopping the study). Less extreme 
observations (eg, mild) may not require discontinuing the study vaccine but can still contribute 
to evaluating safety by identifying parameters to focus upon in subsequent product 
development. Uniform criteria for categorising toxicities in healthy volunteers can improve 
comparisons of safety data among groups within the same study and also between different 
studies. We, FDA, recommend using toxicity grading scale tables, provided below, as a guideline 
for selecting the assessment criteria to be used in a clinical trial of a preventive vaccine. We 
recommend incorporation of such appropriate, uniform, criteria into the investigational plan, 
case report forms, and study reports and correspondence with FDA, sponsors, monitors, 
investigators, and IRBs. 
This guidance finalizes the draft guidance of the same title dated April 2005 (70 FR 22664, May 
2, 2005). 
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this 
topic. It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public. You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations. If you want to discuss an alternative 
approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 


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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 participants. 
Toxicity grading scales for laboratory abnormalities should consider the local laboratory 
reference values when the parameter limit values are defined. The characterisation 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 creatine phosphokinase 
(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 categorise adverse events observed 
during a clinical trial may assist you in monitoring safety and making required reports. 
Nonetheless, we believe that categorisation 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 to include additional parameters to be monitored during a clinical trial or to alter 


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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 preclinical toxicology studies, 
the biological plausibility of the occurrence of certain adverse events, or previous experience 
with a similar licenced 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 
* Participants 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 judgement when characterising bradycardia 
among some healthy participant 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 
Diarrhea 
2 – 3 loose stools or 
<400 gms/24 hours 
4 – 5 stools or 
400 – 800 gms/ 
24 hours 
6 or more 
watery stools or 
>800 gms/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. 
Serum1 
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)2 
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 
ULN3 
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 
1 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. 
2 The clinical signs or symptoms associated with laboratory abnormalities might result in characterisation 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 participant had a new seizure 
associated with the low sodium value. 
3ULN is the upper limit of the normal range. 


I N D V-2 0 0 0  
Cli nic al St u dy Pr ot oc ol: I N D V -2 0 0 0 -1 0 5 Fi n al  
I n di vi or 
1 5  M a y 2 0 2 3  
 
C o nfi d e nti al  
P a g e 7 5  of 7 8 
H e m at ol o g y 1 
Mil d ( Gr a d e 1)  
M o d er at e 
( Gr a d e 2) 
S e v er e ( Gr a d e 3)  P ot e nti all y 
Lif e-
T hr e at e ni n g  
( Gr a d e 4) 
H e m o gl o bi n ( F e m al e) - g m/ dL  
1 1. 0 –  1 2. 0  
9. 5 –  1 0. 9  
8. 0 –  9. 4  
<. 0  
H e m o gl o bi n ( F e m al e)  
c h a n g e fr o m b as eli n e 
v al u e - g m/ dL  
A ny d ecr e as e –  
1. 5  
1. 6 –  2. 0  
2. 1 –  5. 0  
>. 0  
H e m o gl o bi n ( M al e) - g m/ dL  
1 2. 5 –  1 3. 5  
1 0. 5 –  1 2. 4  
8. 5 –  1 0. 4  
< 8. 5  
H e m o gl o bi n ( M al e)  
c h a n g e fr o m b as eli n e 
v al u e  –  g m/ dL  
A ny d ecr e as e –  
1. 5  
1. 6 –  2. 0  
2. 1 –  5. 0  
> 5. 0  
W B C I ncr e as e - c ell/ m m 3 
1 0, 8 0 0 –  1 5, 0 0 0  
1 5, 0 0 1 –  2 0, 0 0 0  
2 0, 0 0 1 –  2 5, 0 0 0  > 2 5, 0 0 0  
W B C D ecr e as e - c ell/ m m 3 
2, 5 0 0 –  3, 5 0 0  
1, 5 0 0 –  2, 4 9 9  
1, 0 0 0 –  1, 4 9 9  
< 1, 0 0 0  
L y m p h oc yt es D ecr e as e - c ell/ m m 3 7 5 0 –  1, 0 0 0  
5 0 0 –  7 4 9  
2 5 0 –  4 9 9  
< 2 5 0  
N e utr o p hils D ecr e as e - c ell/ m m 3 1, 5 0 0 –  2, 0 0 0  
1, 0 0 0 –  1, 4 9 9  
5 0 0 –  9 9 9  
< 5 0 0  
E osi n o p hils - c ell/ m m 3 
6 5 0 –  1 5 0 0  
1 5 0 1 - 5 0 0 0  
> 5 0 0 0  
H y p er e osi n o p hilic  
Pl at el ets D ecr e as e d - c ell/ m m 3 
1 2 5, 0 0 0 –  
1 4 0, 0 0 0  
1 0 0, 0 0 0 –  1 2 4, 0 0 0  
2 5, 0 0 0 –  9 9, 0 0 0  
< 2 5, 0 0 0  
P T –  i ncr e as e by f act or 
( pr ot hr o m bi n ti m e) 
1. 0 –  1. 1 0 x  
UL N 2 
1. 1 1 –  1. 2 0 x UL N  
1. 2 1 –  1. 2 5 x UL N  > 1. 2 5 UL N  
P T T –  i ncr e as e b y f act or 
( p arti al t hr o m b o pl asti n 
ti m e) 
1. 0 –  1. 2 x UL N  
1. 2 1 –  1. 4 x UL N  
1. 4 1 –  1. 5 x UL N  
> 1. 5 x UL N  
Fi bri n o g e n i ncr e as e - m g/ dL  
4 0 0 –  5 0 0  
5 0 1 –  6 0 0  
> 6 0 0  
-- 
Fi bri n o g e n d ecr e as e - m g/ dL  
1 5 0 –  2 0 0  
1 2 5 –  1 4 9  
1 0 0 –  1 2 4  
< 1 0 0 or 
ass oci at e d wit h 
gr oss bl e e di n g 
or diss e mi n at e d 
i ntr a v asc ul ar 
c o a g ul ati o n ( DI C) 
1 T h e l a b or at ory v al u es pr o vi d e d i n t h e t a bl es s erv e as g ui d eli n es a n d ar e d e p e n d e nt u p o n i nstit uti o n al n or m al 
p ar a m et ers. I nstit uti o n al n or m al r ef er e nc e r a n g es s h o ul d b e pr o vi d e d t o d e m o nstr at e t h at t h e y ar e  a p pr o pri at e.  
2 “ UL N” is t h e u p p er li mit of t h e n or m al r a n g e. 
 
Uri n e 1 
Mil d ( Gr a d e 1)  
M o d er at e 
( Gr a d e 2) 
S e v er e ( Gr a d e 3)  P ot e nti all y 
Lif e-
T hr e at e ni n g 
( Gr a d e 4) 
Pr ot ei n  
Tr ac e  
1 +  
2 +  
H os pit aliz ati o n or  
di al ysis  
Gl uc os e  
Tr ac e  
1 +  
2 +  
H os pit aliz ati o n 
f or 
h y p er glyc e mi a  
Bl o o d 
( micr osc o pic) – 
r e d bl o o d c ells 
p er  
hi g h p o w er fi el d (r bc/ h pf) 
1 - 1 0  
1 1 –  5 0  
> 5 0 a n d/ or 
gr oss bl o o d  
H os pit aliz ati o n 
or p ack e d r e d 
bl o o d c ells 
( P R B C) 
tr a nsf usi o n 
1 T h e l a b or at ory v al u es pr o vi d e d i n t h e t a bl es s erv e as g ui d eli n es a n d ar e d e p e n d e nt u p o n i nstit uti o n al n or m al 
p ar a m et ers. I nstit uti o n al n or m al r ef er e nc e r a n g es s h o ul d b e pr o vi d e d t o d e m o nstr at e t h at t h e y ar e a p pr o pri at e.  


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IV. 
References 
1. National Cancer Institute Common Toxicity Criteria, April 30, 1999. 
(http://ctep.cancer.gov/reporting/CTC-3.html) 
2. Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 1992. 
(http://rcc.tech-res-intl.com/tox_tables.htm) 
3. The Brighton Collaboration. Finalized Case Definitions and Guidelines. 
(http://brightoncollaboration.org/internet/en/index/definition___guidelines.html) 
4. HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; September 
18, 2002. (http://rcc.tech-res-intl.com/tox_tables.htm) 
5. 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/DAIDSAEGradi
ngTable.pdf) 
6. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. New England 
Journal of Medicine. 2004;351:1548-1563. 
 
 
 


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10.6 REFERENCES 
 
Azizi H, Mirnajafi-Zadeh J, Rohampour K, Semnanian S. Antagonism of orexin type 1 receptors in 
the locus coeruleus attenuates signs of naloxone-precipitated morphine withdrawal in rats. 
Neurosci Lett. 2010;482:255-9. 
 
Coleman PJ, Gotter AL, Herring WJ, Winrow CJ, Renger JJ. The discovery of suvorexant, the first 
orexin receptor drug for insomnia. Annu Rev Pharmacol Toxicol. 2017;57:509-33.  
 
Dunn KE, Huhn AS, Bergeria CL, Gipson CD, Weerts EM. Non-Opioid Neurotransmitter Systems 
that Contribute to the Opioid Withdrawal Syndrome: A Review of Preclinical and Human 
Evidence. J Pharmacol Exp Ther. 2019;371:422-52. 
 
Flockhart DA, Thacker, D., McDonald, C., Desta, Z. The Flockhart Cytochrome P450 Drug-Drug 
Interaction Table. Division of Clinical Pharmacology, Indiana University School of Medicine 
(Updated 2021). Availabe from: https://drug-interactions.medicine.iu.edu/. Accessed on: 12 
May 2023. 
 
Food and Drug Administration: Center for Drug Evaluation and Research (CDER). Guidance for 
Industry: Clinical Pharmacology Considerations for Human Radiolabelled Mass Balance Studies 
(May 2022). Accessible on the page https://www.fda.gov/media/158178/download. Accessed 
on: 12 May 2023. 
 
Food and Drug Administration CFR - Code of Federal Regulations Title 21, Volume 5, Revised as 
of January 17, 2023 [CITE: 21CFR361.1] accessible on the page: 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ 
CFRSearch.cfm?CFRPart=361&showFR=1. Accessed on: 12 May 2023. 
 
Hooshmand B, Azizi H, Javan M, Semnanian S. Intra-LC microinjection of orexin type-1 receptor 
antagonist SB-334867 attenuates the expression of glutamate-induced opiate withdrawal like 
signs during the active phase in rats. Neurosci Lett. 2017;636:276-81. 
 
ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological 
Protection. ICRP Publication 103. Ann. ICRP 37 (2-4). Accessible at 
http://journals.sagepub.com/doi/pdf/10.1177/ANIB_37_2-4. Accessed on: 12 May 2023. 
 
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. 


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Markham, A. Daridorexant: First Approval. Drugs 2022;82:601–7. 
 
Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, Dhadda S, Hong Q, Giorgi 
L, Satlin A. Lemborexant, a dual orexin receptor antagonist (DORA) for the treatment of 
insomnia disorder: results from a Bayesian, adaptive, randomized, doubleblind, placebo-
controlled study. J Clin Sleep Med. 2017;13:1289-99  
 
National Council on Radiation Protection and Measurements (NCRP) Report No. 160, Ionizing 
Radiation Exposure of the Population of the United State, National Council on Radiation 
Protection and Measurements, March 2009. 
 
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;10:447. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN: INDV-2000-105
Protocol Title:  A Phase I, Open Label Study to Assess the 
Absorption, Metabolism, Excretion, and Mass Balance of a Single 
dose of Oral [14C]-IDV184001AN in Healthy Adult Male 
Participants 
Final Version: 15 May 2023
NCT: NCT05974046 


SAP for Protocol INDV-2000-105 
INDV-2000 
Statistical Analysis Plan 
Protocol Title: 
A Phase I, Open Label Study to Assess the Absorption, 
Metabolism, Excretion, and Mass Balance of a Single dose of 
Oral [14C]-IDV184001AN in Healthy Adult Male Participants 
Protocol Number: 
INDV-2000-105 
Compound Number: 
INDV-2000 
Sponsor Name: 
Indivior 
Legal Registered Address:  10710 Midlothian Turnpike, Suite 125 
North Chesterfield, VA 23235 
USA 
IND Number: 
145881 
Protocol Version: 
Original 
Date: 
15 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-2000-105 
INDV-2000 
Statistical Analysis Plan Approval 
Submitted by: 
Approved by: 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
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 ..................................................................................................................... 10 
2. STATISTICAL HYPOTHESES .......................................................................................... 11 
2.1. Multiplicity Adjustment .................................................................................................... 11 
3. SAMPLE SIZE DETERMINATION ................................................................................... 11 
4. POPULATIONS FOR ANALYSIS ..................................................................................... 11 
5. STATISTICAL ANALYSES ............................................................................................... 12 
5.1. General Considerations ..................................................................................................... 12 
5.1.1. Timing of Analyses .................................................................................................. 12 
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. Secondary Endpoints Analysis .......................................................................................... 14 
5.4.1. Definition of Endpoints ............................................................................................ 14 
5.4.2. Main Analytical Approach ....................................................................................... 14 
5.5. Tertiary/Exploratory Endpoints Analysis .......................................................................... 14 
5.5.1. Definition of Endpoints ............................................................................................ 14 
5.5.2. Main Analytical Approach ....................................................................................... 15 
5.6. Other Safety Analyses ....................................................................................................... 15 
5.6.1. Study Drug Exposure ............................................................................................... 15 
5.6.2. Adverse Events ......................................................................................................... 15 
5.6.3. Additional Safety Assessments ................................................................................ 16 


SAP for Protocol INDV-2000-105 
INDV-2000 
 ............................................................................................... 16 
 ....................................................................................................... 18 
 ....................................................................... 18 
 ....................................... 18 
5.7. Other Analyses .................................................................................................................. 19 
5.7.1. Demographics and Anthropometrics ........................................................................ 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 ........................................................ 21 
6.3. Appendix 3: Definition and Use of Visit Windows in Reporting ..................................... 22 
6.4. Appendix 4: Endpoint Derivations .................................................................................... 22 
6.4.1. Mass Balance and PK Endpoints ............................................................................. 22 
6.4.1.1. Urine and Feces Mass Balance and PK Parameters ........................................ 22 
6.4.1.2. Plasma and Whole Blood PK Parameters ....................................................... 22 
6.4.1.3. Metabolite Identification, Profiling and Quantitation ..................................... 23 
6.4.1.4. Whole Blood to Plasma Partitioning Ratio ..................................................... 23 
6.5. Appendix 5: Statistical Methodology Details ................................................................... 24 
6.5.1.1. Concentrations and Concentration Equivalents .............................................. 24 
6.5.1.2. Mass Balance and PK Parameters ................................................................... 24 
6.6. Appendix 6: Methods to Manage Missing Data ................................................................ 25 
6.6.1. BLQ PK Concentrations and Concentration Equivalents ........................................ 25 
6.6.2. AEs ........................................................................................................................... 25 
6.6.3. Medications and Therapies ....................................................................................... 26 
6.7. Appendix 7: Data Set Descriptions ................................................................................... 27 
7. REFERENCES ..................................................................................................................... 28 


SAP for Protocol INDV-2000-105 
INDV-2000 
LIST OF TABLES 
Table 1 
SAP Version History Summary .................................................................. 6 
Table 2 
Study Objectives and Estimands ................................................................. 7 
Table 3 
Analysis Populations ................................................................................. 11 
Table 4 
Planned Laboratory Evaluations ............................................................... 17 
Table 6 
Mass Balance and PK Parameters : TRA – Urine, Feces, and Urine 
+ Feces ...................................................................................................... 22 
Table 5 
PK Parameters: TRA, Unlabeled Plasma IDV184001, and 
Unlabeled Plasma M12 – Plasma and Whole Blood ................................ 22 
LIST OF FIGURES 
Figure 1. 
Study Schematic ........................................................................................ 10 


SAP for Protocol INDV-2000-105 
INDV-2000 
1. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study INDV-2000-105 and is based on the original 
protocol dated 15May2023. This SAP supersedes the statistical considerations stated in the 
protocol; any differences are identified in Section 6.2 (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). 
Note: INDV-2000 is the current name for the IDV184001 drug compound, and IDV184001 
is the active moiety of IDV184001AN. 
VERSION HISTORY 
Table 1   SAP Version History Summary 
SAP 
Version 
SAP 
Finalization 
Date 
Associated 
Protocol 
Version 
Protocol 
Approval 
Date 
Change 
Rationale 
1.0 
15Nov2023 
Original 
15May2023 
Not Applicable 
Original version 
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) and mass balance endpoints in that only 
subjects with an adequate amount of PK and mass balance data will be included in the PK 
Analysis Set (Table 3); for all other endpoints, the treatment policy strategy will be used and 
all available data will be summarized. Other potential intercurrent events in this study are 
prohibited medications and lifestyle restrictions detailed in protocol sections 6.9 and 5.3, 
respectively. Possible strategies for these intercurrent events are treatment policy 
(intercurrent event is ignored), while on treatment (data collected after the event would be 
ignored), and principal stratum for PK and mass balance endpoints (subject would be 
excluded from the PK Analysis Set), to be decided by the sponsor on a case-by-case basis. 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
 
 
 
Table 2 
Study Objectives and Estimands 
 
Estimand 
Objective 
Clinical Category 
Statistical 
Category 
Variable/Endpoint 
Pop- 
ulation 
Population-Level Summary 
Primary Objectives 
• 
To investigate the route(s) of elimination and the overall mass balance of IDV184001, following a single oral dose of [14C]- 
IDV184001AN in healthy adult male participants. 
• 
To quantitate total radioactivity (TRA) in whole blood, plasma, urine, and feces following a single oral dose of [14C]-IDV184001AN in 
healthy adult male participants. 
• 
To characterise the PK profile of unlabeled IDV184001 and M12 in plasma following a single oral dose of [14C]- IDV184001AN in 
healthy adult male participants. 
• 
To perform metabolite identification, profiling and quantitation for IDV184001 in plasma, urine, and feces following a single oral dose of 
[14C]-IDV184001AN in healthy adult male participants. 
• 
To determine the ratio of TRA concentration equivalents in whole blood versus plasma following a single oral dose of [14C]- 
IDV184001AN in healthy adult male participants. 
PK 
Primary 
TRA recovery and the percent of the radioactive dose excreted 
in the urine, feces, and urine+feces: % Dose, Cum%Dose 
[Time Frame: Pre-dose to 168 hours post-dose, collection time 
can be extended]. 
PK 
Numeric descriptive 
TRA PK parameters in plasma and whole blood: AUClast, 
AUC0-∞, AUCextrap(%), Cmax, Tmax, λz, and T1/2 as data permit 
[Time Frame: Pre-dose to 168 hours post-dose, collection time 
can be extended]. 
PK 
Numeric descriptive (median 
and range only for Tmax) 
TRA PK parameters in urine, feces, and urine+feces: Aet1-t2, 
CumAe, and CLr (urine only) [Time Frame: Pre-dose to 168 
hours post-dose, collection time can be extended]. 
PK 
Numeric descriptive 
Unlabeled IDV184001 and M12 PK parameters in plasma: 
AUClast, AUC0-∞, AUCextrap(%), Cmax, Tmax, λz, T1/2, as data 
permits [Time Frame: Pre-dose to 168 hours post-dose]. 
PK 
Numeric descriptive (median 
and range only for Tmax) 
Ratio of unlabeled IDV184001 and M12 in plasma to plasma 
TRA for AUClast and Cmax, where appropriate [Time Frame: 
Pre-dose to 168 hours post-dose]. 
PK 
Numeric descriptive 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
 
 
 
Objective 
Clinical Category 
Statistical 
Category 
Variable/Endpoint 
Pop- 
ulation 
Population-Level Summary 
PK (continued) 
Primary 
(continued) 
Identification of parent and metabolites in plasma, urine, and 
feces. 
Descriptive 
% of AUC of each metabolite in plasma, % of dose of each 
metabolite in urine, % of dose of each metabolite in feces 
[Time Frame: Pre-dose to 168 hours post-dose, collection time 
can be extended] 
PK 
Numeric descriptive 
The ratio of TRA concentration equivalents in whole blood 
relative to plasma at each time matched determination of TRA 
in whole blood and plasma [Time Frame: Pre-dose to 168 hours 
post-dose, collection time can be extended]. 
PK 
Numeric descriptive 
Secondary Objective 
• 
To assess the safety and tolerability of a single oral dose of [14C]-IDV184001AN as determined by adverse event (AE) reporting. 
Safety 
Secondary 
Incidence, seriousness, severity, and relatedness of treatment- 
emergent AEs (TEAEs). 
Safety 
Categorical descriptive 
Tertiary/Exploratory Objective 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
 
 
Estimand 
Objective 
Clinical Category 
Statistical 
Category 
Variable/Endpoint 
Pop- 
ulation 
Population-Level Summary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
1.2. Study Design 
This is a Phase I open-label, single-center, single-dose study in healthy adult male 
participants to characterize the absorption, metabolism, excretion, and mass balance of 
[14C]-IDV184001. 
The study schematic is depicted in Figure 1. 
Figure 1. Study Schematic 
 
 
 
Key features of the study design are described below. 
• Approximately 7 healthy adult males will be enrolled to ensure at least 6 participants 
complete the study. 
• On Day 1, participants will receive a single oral dose of 200 mg (~100 µCi) [14C]- 
IDV184001AN. 
• Blood (for plasma and whole blood), urine, and fecal samples will be collected pre-dose 
and for at least 168 hours post-dose (ie, Day 8) to measure TRA (all sample matrices), 
and for metabolite identification, profiling and quantitation (plasma, urine, and feces), as 
appropriate. Blood samples for plasma concentrations of unlabeled IDV184001 and M12 
will also be collected for at least 168 hours post-dose. 
• Participants may be discharged from the study site following the 168-hour post-dose 
blood draw and/or study procedures on Day 8, if at least one discharge criterion is met 
(refer to Protocol Section 4.1.1
 If neither 
discharge criterion is met by 168 hours post-dose (ie, Day 8), participants will remain 
confined at the study site until at least one discharge criterion is met or a maximum stay 
of 21 days post-dose is reached (ie, Day 22), whichever is first. 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
• For participants who remain confined past Day 8, collection of urine and fecal samples 
for TRA determination and metabolite identification, profiling and quantitation will 
continue in 24-hour intervals and collection of blood for TRA determination (whole 
blood and plasma) and metabolite identification, profiling and quantitation (plasma) will 
continue in 72-hour intervals. 
• The total planned study duration for each participant will be up to 7 weeks. This includes 
a screening period of up to 4 weeks and a treatment period of at least 1 week (Days 1 to 
8) up to a maximum of 3 weeks (Days 1 to 22) until at least one discharge criterion is 
met. 
2. STATISTICAL HYPOTHESES 
There are no formal statistical hypotheses for this study. 
2.1. Multiplicity Adjustment 
There will be no formal statistical inference in this study; therefore, there will be no 
multiplicity adjustment. 
3. SAMPLE SIZE DETERMINATION 
Approximately 7 participants will be enrolled to ensure 6 participants complete the study. 
The sample size was selected without statistical considerations. It has been determined 
adequate to meet the study objectives and is in accordance with the Food and Drug 
Administration guidance.1, 2 This sample size is limited based on clinical considerations for 
this type of study and in order to limit exposure to radioactivity. 
 
4. POPULATIONS FOR ANALYSIS 
Data for all participants will be assessed to determine if they meet the criteria for inclusion in 
each analysis population shown in Table 3 prior to releasing the database. Classifications will 
be documented per standard operating procedures. 
Table 3   Analysis Populations 
 
Population 
Description 
Screened 
Participants who signed informed consent. 
Safety Analysis Set 
Participants who received the study drug. 
PK Analysis Set 
Participants who received the study drug and had an adequate 
number of PK samples collected to derive any ADME 
(absorption, distribution, metabolism and excretion) parameter 
and have no protocol deviations that would significantly alter 
disposition of study drug. 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
5. STATISTICAL ANALYSES 
5.1. General Considerations 
5.1.1. Timing of Analyses 
Safety data will be reviewed on an ongoing basis. There will be a production run of tables, 
figures, and listings (TFLs) after the database has been locked following the study-level 
EOS. 
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, where 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: 
• Tables and figures will present summaries/analyses by study visit and time point, as 
appropriate. 
• Table column headers and figure legends will include sample size (“N = xx”), where 
applicable. Sample sizes reported as part of descriptive statistics (“n”) will be the number 
of non-missing observations. 
• Listings will generally include unique subject identifier; 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 original data. The number of decimal places for 
means, medians, and interquartile ranges will be the same as the original data plus one, and 
the number of decimal places for measures of variance will be the same as the source data 
plus two. See Appendix 6.4.1 (Appendix 4) 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 
Study Drug: IDV184001AN + [14C]-IDV184001AN 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
Screening Period: Informed consent to Day -1 Clinic Check-In. 
Day -1 Clinic Check-In: clinic check-in to date/time of dosing on Day 1. 
Study Day 1: day of study drug dosing. 
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 
Duration: 
• Duration in days = end date – start date + 1 
• Duration in minutes = end time – start time 
Baseline observation: for a given parameter for a given subject, the last observed value, 
including unscheduled and repeated assessments, before study drug dosing. 
EOS, Subject-Level: Early termination or completion of discharge criteria or completion of a 
21-day clinic stay post-dose (ie, Study Day 22). 
EOS, Study-Level: Study completion for the last subject. 
5.2. Study Conduct and Participant Disposition 
Subject disposition summaries will include the number of subjects screened and the number 
and percentage of subjects who were screen failures, who were otherwise not enrolled, 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 failures, for 
subjects not otherwise enrolled, and for subjects who were enrolled, and the number of 
subjects enrolled will be the denominator for the Safety Analysis Set, the PK Analysis Set 
and for subjects completing the study. 
Reason for study discontinuation will also 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 and other non-enrollment will be summarized in a separate table by 
number and percentage of subjects for each reason reported; the denominator will be the 
number of non-enrolled subjects. 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
5.3. Primary Endpoints Analysis 
5.3.1. Definition of Endpoints 
The primary endpoints are itemized in Table 2. 
5.3.2. Main Analytical Approach 
Estimand strategy: Principal stratum. 
Analysis set: PK (see Table 3). 
Analysis methodology: 
For TRA recovery and the percentage of the radioactive dose excreted in the urine, feces, and 
in both excreta combined (mass balance), based on urine sample weights, fecal homogenate 
weights, IDV184001-concentration equivalents of TRA in urine and fecal homogenate 
samples collected at each interval will be used to derive the TRA recovery parameters for 
each subject using standard non-compartmental methods (see Appendix 6.4.2.2). 
For PK analysis, standard non-compartmental methods based on actual sampling times will 
be used to derive parameters for each subject (see Appendix 6.4.2.1). 
Intercurrent events and missing data: Subjects with intercurrent events may be excluded from 
the PK Analysis Set, 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. 
5.4. Secondary Endpoints Analysis 
5.4.1. Definition of Endpoints 
The secondary endpoints are incidence, seriousness, severity, and relatedness of TEAEs. 
5.4.2. Main Analytical Approach 
Estimand strategy: Treatment policy. 
Analysis set: Safety (see Table 3). 
Analysis methodology: Descriptive only. 
Intercurrent events and missing data: AEs will be reported regardless of the occurrence of an 
intercurrent event. See Section 6.6.2 (Appendix 6) for handling of missing AE information. 
See Section 5.5.2 for details on AE summaries and listings. 
5.5. Tertiary/Exploratory Endpoints Analysis 
5.5.1. Definition of Endpoints 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
5.5.2. Main Analytical Approach 
5.6. Other Safety Analyses 
5.6.1. Study Drug Exposure 
Details of study drug exposure will be listed and summarized. Exposure data will be 
presented with the same precision as original data in listings, and will be rounded to 2 or 3 
decimal places for summarization, depending on the data. 
5.6.2. Adverse Events 
A TEAE starts at or after study drug dosing. 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 study drug; 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 
study discontinuation, and fatal TEAEs will be listed separately. 
The incidence and number of all TEAEs, TESAEs, study drug-related TEAEs and study 
drug-related TESAEs, severe TEAEs, TEAEs with grade 3 or higher toxicity grade, TEAEs 
leading to study discontinuation, and fatal TEAEs will be presented in an overall summary 
table. 
TEAEs, TESAEs, study drug-related TEAEs and study drug-related TESAEs will be 
summarized by MedDRA SOC and PT, each in descending order of frequency among all 
subjects (then alphabetically in case of ties). TEAEs will also be summarized by maximum 
severity and by maximum toxicity 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 tables. 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
Incidence and number of TEAEs will also be summarized by PT only (ie, not SOC), sorted 
by descending frequency among all subjects. 
Non-TEAEs are defined as AEs that started before study drug dosing. Non-TEAEs will be 
summarized for the Safety Analysis Set. 
See Section 6.6.2 (Appendix 6) for details on handling of missing AE information. 
5.6.3. Additional Safety Assessments 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
5.7. Other Analyses 
5.7.1. Demographics and Anthropometrics 
Demographics and anthropometrics will be summarized separately for the safety and PK 
analysis sets, if different. Parameters to be summarized will include age, race, ethnicity, and 
height/weight/body mass index. 
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 analysis set. 
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 ended before dosing or were taken by subjects who were 
never dosed. All other medications and therapies will be considered concomitant. 
Prior and concomitant medications and therapies will be summarized separately for the safety 
analysis set. The summary of incidence (number and percentage of subjects reporting the 
medication or therapy at least once) will be sorted alphabetically by therapeutic class (ATC 
level 2) and standardized medication/therapy name. 
See Section 6.6.3 (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, important, not important), per the Protocol Deviation Assessment Tool for the study, for 
the safety analysis set. Deviations that occur in subjects who were not in the safety analysis 
set, 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-2000-105 
INDV-2000 
 
 
6.1. Appendix 1: List of Abbreviations 
 
Abbreviation 
Term 
%DoseAe 
percent of administered dose excreted/recovered within a given 
collection interval 
ADaM 
Analysis Data Model 
ADME 
absorption, distribution, metabolism and excretion 
AE 
adverse event 
Aet1-t2 
amount of total radioactivity excreted/recovered within a given 
collection interval 
ATC 
Anatomic Therapeutic Chemical 
AUC 
area under the curve 
AUC0-∞ 
area under the curve from 0 to infinity 
AUCextrap(%) 
area under the curve extrapolated as a percentage of the total AUC0-∞ 
AUClast 
area under the curve from dosing to the last measured concentration 
BLQ 
below limit of quantitation 
 
 
Cmax 
maximum plasma concentration 
CL/F 
apparent total clearance of drug from plasma after oral administration 
CLr 
renal clearance 
CRF 
Case Report Form 
CSR 
clinical study report 
Cum%Dose 
cumulative percent of dose excreted/recovered 
CumAe 
cumulative amount of total radioactivity excreted/recovered 
CV 
coefficient of variation 
 
 
EOS 
end of study 
HPLC 
high-performance liquid chromatography 
λz 
terminal elimination rate constant 
µCi 
microcurie 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRAUC0-∞ 
metabolic ratio of AUC0-∞ 
MRCmax 
metabolic ratio of Cmax 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
 
 
RAUClast (plasma) 
ratio of unlabeled plasma drug AUClast to plasma TRA AUClast 
RCmax (plasma) 
ratio of unlabeled plasma drug Cmax to plasma TRA Cmax 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
T1/2 
apparent terminal half-life 
Tmax 
time of maximum plasma concentration 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
TRA 
total radioactivity 
Vz/F 
apparent volume of distribution during the terminal elimination phase 
after oral administration 
WHO-DD 
World Health Organization Drug Dictionary 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
6.2. Appendix 2: Changes to Protocol-Planned Analyses 
The following are changes from the protocol that are in the SAP: 
 
Protocol: 
SAP (changes in bold): 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
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). An early termination visit will be counted as a scheduled visit if it occurs 
on a scheduled visit study day; otherwise, it will be counted as an unscheduled visit. 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. Mass Balance and PK Endpoints 
Individual plasma, and whole blood, urine, and feces samples are collected according to the 
schedules outlined in Section 10.4 of the protocol. 
6.4.1.1. Urine and Feces Mass Balance and PK Parameters 
TRA recovery and the percent of the radioactive dose excreted in the urine and feces from 
pre-dose to at least 168 hours, as applicable, will be assessed on a per participant basis. Mass 
balance will be calculated as a sum of the percent of the TRA recovered in urine and feces 
relative to the administered radioactive dose. If emesis occurs, the calculation of mass balance 
may take into account any radioactivity recovered in the vomitus as appropriate. 
Urine, feces, and urine + feces parameters to be calculated are shown in Table 6. Additional 
parameters may be calculated if required. 
Table 5 
Mass Balance and PK Parameters : TRA – Urine, Feces, and Urine + Feces 
 
Parameter 
Definition 
Aet1-t2 
Amount of total radioactivity excreted/recovered within a given collection interval 
CumAe 
Cumulative amount of total radioactivity excreted/recovered 
%DoseAe 
Percent of administered dose excreted/recovered within a given collection interval 
Cum%Dose 
Cumulative percent of dose excreted/recovered 
CLr 
Renal clearance. CLr = CumAeAet1-t2/AUC, where both CumAeAet1-t2 and AUC are 
determined over matched time interval (urine only) 
 
6.4.1.2. Plasma and Whole Blood PK Parameters 
Plasma and whole blood PK parameters to be calculated are shown in Table 5. Additional 
parameters may be calculated if required. 
Table 6 
PK Parameters: TRA, Unlabeled Plasma IDV184001, and Unlabeled Plasma 
M12 – Plasma and Whole Blood 
 
Parameter 
Definition 
Cmax 
Maximum observed concentration 
Tmax 
Time of maximum observed concentration 
AUClast 
Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration; calculated using the linear trapezoidal rule 


SAP for Protocol INDV-2000-105 
INDV-2000 
 
 
 
Parameter 
Definition 
AUC0-∞ 
Area under the concentration-time curve from time 0 extrapolated to infinite time 
AUCextrap(%) 
Percent of the area under the concentration-time curve due to extrapolation 
λz 
Terminal phase rate constant 
t1/2 
Apparent terminal half-life 
CL/F 
Apparent total clearance after oral (extravascular) administration, calculated as Dose/ 
AUC0-∞ (parent only) 
Vz/F 
Apparent volume of distribution during the terminal elimination phase after oral 
(extravascular) administration, calculated as Dose/(AUC0-∞  λz) (parent only) 
MRAUC0-∞ 
Metabolic ratio of the metabolite AUC0-∞ to the parent AUC0-∞ 
MRCmax 
Metabolic ratio of the metabolite Cmax to the parent Cmax 
RAUClast (plasma) 
Ratio of unlabeled plasma drug AUClast to plasma TRA AUClast 
RCmax (plasma) 
Ratio of unlabeled plasma drug Cmax to plasma TRA Cmax 
 
To calculate the slope of the terminal phase (λz), the following acceptance criteria will be 
used: 
• 
Rsq ≥ 0.80 
• 
Minimum of three time points in the terminal phase (not including Cmax) 
• 
AUC0-inf will be calculated if the percentage of AUC extrapolation (AUCextrap(%)) is 
<=20% 
Actual sampling times will be used in PK parameter calculations. 
6.4.1.3. Metabolite Identification, Profiling and Quantitation 
IDV184001 metabolite identification, profiling and quantitation will be performed on plasma, 
urine, and fecal samples from pre-dose to at least 168 hours, as applicable, containing 
sufficient amounts of radioactivity. For metabolite profiling in urine and feces, collected 
samples will be pooled across the time intervals for each subject to account for ~90% of the 
radioactivity excreted in a given matrix. Pooling will be conducted in proportion to the 
amount (weight or volume) of excreta collected in each sampling period. For metabolite 
profiling in collected plasma, samples will be pooled across time points for each subject 
according to the AUC pooling formula.3 Typically, ≥ 90% of the radioactivity contained 
within a pooled matrix is extracted for analysis. The percent of dose in urine and feces and % 
of AUC in plasma represented by each of the metabolites will be calculated. 
Radiochromatographic peaks from high-performance liquid chromatography (HPLC) coupled 
with radiodetection will be integrated and the quantity of each identified metabolite is 
reported as % dose for excreta and % AUC in plasma, relative to total radioactivity. The % of 
AUC plasma will also be calculated relative to % of AUC for parent. 
6.4.1.4. Whole Blood to Plasma Partitioning Ratio 
The ratio of TRA concentration equivalents in whole blood relative to plasma at each 
time-matched determination of TRA in whole blood and plasma from pre-dose to at least 
168 hours, as applicable, will be calculated. 


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6.5. Appendix 5: Statistical Methodology Details 
Statistical programming, including urine and feces PK parameters, will be done using SAS® 
version 9.4 (or higher). Plasma and whole blood PK parameters will be calculated using 
Phoenix™ WinNonlin® (Version 8.3.4 or higher, Certara, LP). 
6.5.1.1. Concentrations and Concentration Equivalents 
For plasma and whole blood, listings of individual TRA concentration equivalents and 
unlabeled IDV184001 and M12 concentrations from pre-dose to at least 168 hours, as 
applicable, at scheduled collection times points will include nominal time point, sampling 
date and time, time since dosing, deviation from scheduled sampling time, permitted time 
window, and concentration (or concentration equivalent) of each analyte. A separate listing 
will show unscheduled collections. Time since dosing (hour) will be calculated as the 
sampling date and time – dosing date and time and will be rounded to two decimal places. For 
scheduled time points, time deviation (minute) will be calculated as sampling date and time – 
(dosing date and time + nominal sampling time). 
 
For urine and feces, listings of individual TRA concentration equivalents from pre-dose to at 
least 168 hours, as applicable, at scheduled collection intervals will include collection 
interval, start and end date and time of the interval, weight collected, and concentration 
equivalent. 
 
Concentrations and concentration equivalents will be reported in listings with the same 
precision as the source data provided by the bioanalytical laboratory. Data will be 
summarized using arithmetic means, SDs, medians, ranges, and coefficients of variation 
(CVs) by analyte and nominal time point or collection interval. Means, ranges, and medians 
will be reported to three significant digits; SDs will be reported to four significant digits; and 
CVs will be rounded to 1 decimal place. 
 
Individual and mean (± SD) concentrations and concentration equivalents in whole blood and 
plasma versus time plots will be presented on linear and semi-logarithmic scales. The x-axis 
will represent actual time since dosing in individual plots and nominal time point in mean 
plots. 
Methods for handling concentration and concentration equivalent values reported as below 
limit of quantitation (BLQ) are described in Section 6.6.1 (Appendix 6). 
6.5.1.2. Mass Balance and PK Parameters 
Mass balance and PK parameters will be reported with the following precision in data listings: 
Cmax will be reported with the same precision as the source data; Tmax, ratios, and percentages 
will be reported to 2 decimal places, and reporting precision for mass balance and all other PK 
parameters (λz, CL/F, Vz/F, Aet1-t2, CumAe, and CLr) will depend on the minimum observed 
value. For parameters with minimum observed value ≥ 100, observed values will be rounded 
to the nearest integer. For parameters with minimum observed value < 100 but ≥ 10, observed 
values will be rounded to the nearest tenth. For parameters with minimum observed value 
< 10 but ≥ 1, observed values will be rounded to the nearest hundredth. For parameters with 
minimum observed value < 1, observed values will be rounded to the nearest thousandth. If 
any of these rounding rules cannot be applied due to lack of precision in the source data, the 
source data precision will be used. 
Summary tables of mass balance and PK parameters will show arithmetic and geometric 
means and CVs, SDs, medians, and ranges by analyte. Means, ranges, and medians will be 


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reported to three significant digits; SDs will be reported to four significant digits; CVs will be 
rounded to 1 decimal place, and ratios will be rounded to 2 decimal places. Only median and 
range will be reported for Tmax. 
Individual and mean (± SD) percent of Cum%Dose in urine, feces, and urine + feces versus 
time plots will be presented on linear scales. The x-axis will represent the nominal endpoint of 
the collection interval in both individual and mean plots. 
Methods for handling concentration and concentration equivalent values reported as BLQ are 
described in Section 6.6.1 (Appendix 6). 
6.6. Appendix 6: Methods to Manage Missing Data 
6.6.1. BLQ PK Concentrations and Concentration Equivalents 
Concentration and/or concentration equivalent values that are reported as BLQ will be 
presented as “BLQ” in concentration and concentration equivalent listings. For summary 
statistic calculations, concentration and/or concentration equivalent values that are reported as 
BLQ will be set to zero. 
 
For PK parameter derivations and individual subject linear-scale concentration and 
concentration equivalent versus time profiles, all concentrations and concentration equivalents 
that are BLQ prior to the first quantifiable concentration or concentration equivalent will be 
set to zero. All other plasma or blood BLQ values will be set to missing, and all other urine 
or feces BLQ values will be set to zero. BLQ values will be excluded from semi logarithmic- 
scale plots of concentrations and concentration equivalents versus time. No concentration or 
concentration equivalent estimates will be imputed for missing sample values. 
 
6.6.2. 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 
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 
serious adverse event registry. 
 
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. 


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For the Safety Analysis Set, 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 dosing. 
 
• Missing start month, day, time if start year is equal to or after year of dosing, unless it can 
be deduced from non-missing components of AE end date that AE ended before dosing. 
 
• Missing start day and time if start year is after year of dosing or if start year is equal to 
year of dosing and month is equal to or after month of dosing, unless AE end date is 
before date of dosing. 
 
• Missing start time if start date is on or after date of dosing. 
 
6.6.3. Medications and Therapies 
Missing Start and End Date/Time Information for Medications and Therapies 
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 dosing, medication/therapy is prior. 
• If end date is equal to or after date of dosing, medication/therapy is concomitant. 
Non-missing end year and month, missing end day 
• If end year is before year of dosing, medication/therapy is prior. 
• If end year is equal to year of dosing and end month is before month of dosing, 
medication/therapy is prior. 
• If end year is equal to year of dosing and end month is equal to or after month of 
dosing, medication/therapy is concomitant. 
• If end year is after year of dosing, medication/therapy is concomitant. 
Non-missing end year, missing end month and day 
• If end year is before year of dosing, medication/therapy is prior. 
• If end year is equal to or after year of dosing, medication/therapy is concomitant. 
Missing end year, month, and day 
• Medication/therapy is concomitant if subject was dosed; otherwise, 
medication/therapy is prior. 


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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, for example. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. REFERENCES 
1. U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER), Clinical Pharmacology Considerations for 
Human Radiolabeled Mass Balance Studies Guidance for Industry, May 2022. 
 
2. Penner N, Klunk LJ, Prakash C. Human radiolabeled mass balance studies: objectives, 
utilities and limitations. Biopharm Drug Dispos 2009;30(4):185-203. doi: 
10.1002/bdd.661. 
 
3. Hamilton RA, Garnett WR, Kline BJ. Determination of mean valproic acid serum level by 
assay of a single pooled sample. Clin Pharmacol Ther 1981;29(3):408-13. doi: 
10.1038/clpt.1981.56.