Conditions: Healthy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: yes

Brief summary:
The purpose of this study is to investigate the potential for cytochrome P450 (CYP) 3A4 induction after dosing with INDV-2000 via use of midazolam as a probe.

Detailed description:

Arms:
arm 1: Participants will receive a single oral dose of 5 mg midazolam on Day 1. Participants will receive a dose of INDV-2000 twice a day (BID) from Days 2 to 15. On Day 15 participants will also receive a single oral dose of 5 mg midazolam co-administered with the INDV-2000 morning dose.

Interventions: intervention 1: INDV-2000 intervention 2: Midazolam
Intervention descriptions: intervention 1: Capsules administered orally twice a day intervention 2: Midazolam syrup administered orally on Days 1 and 15

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL: INDV-2000-104 
Protocol Title:  An Open Label, Fixed-sequence Study to 
Evaluate the Potential CYP3A4 Induction Effect of INDV-2000 
using Oral Midazolam as a Probe in Healthy Adults Participants 
Protocol Number: INDV-2000-104 
Original Protocol Date: 15 December 2022
Amendment Number/Date: Amendment 1/ 10 April 2023 
NCT: NCT05694533 


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Clinical Study Protocol 
 
PROTOCOL TITLE:  
An Open Label, Fixed-sequence Study to Evaluate the Potential CYP3A4 Induction Effect of 
INDV-2000 using Oral Midazolam as a Probe in Healthy Adults Participants  
Protocol Number: INDV-2000-104 
Amendment Number: 1 
Amendment Scope: Global 
Product: INDV-2000 
Short Title:  
Study of potential CYP3A4 induction by INDV-2000 in healthy adults  
Study Phase: Phase I 
Acronym: DDI 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: 10 Apr 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-2000-104 
Protocol Title: An Open Label, Fixed-sequence Study to Evaluate the Potential CYP3A4 
Induction Effect of INDV-2000 using Oral Midazolam as a Probe in Healthy Adults 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 E6/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 INDV-2000 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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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
Document History 
Document:  
Date 
Amendment 1 
10 Apr 2023 
Original Protocol 
15 Dec 2022 
 
Amendment 1 (10 Apr 2023)  
 
Rationale for the Amendment: 
 
Section Number and Name 
Description of Change 
Brief Rationale 


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Section Number and Name 
Description of Change 
Brief Rationale 


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Section Number and Name 
Description of Change 
Brief Rationale 


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Section Number and Name 
Description of Change 
Brief Rationale 


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Section Number and Name 
Description of Change 
Brief Rationale 


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TABLE OF CONTENTS 
 
MEDICAL MONITOR NAME AND CONTACT INFORMATION .......................................................... 3 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .................................................................... 4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ........................................................... 5 
TABLE OF CONTENTS ................................................................................................................... 10 
TABLE OF TABLES ........................................................................................................................ 13 
TABLE OF FIGURES ...................................................................................................................... 13 
ABBREVIATIONS .......................................................................................................................... 14 
1 PROTOCOL SUMMARY .......................................................................................................... 16 
1.1 Synopsis .......................................................................................................................... 16 
1.2 Schema ............................................................................................................................ 19 
1.3 Schedule of Events (SoE) ................................................................................................. 20 
2 INTRODUCTION ..................................................................................................................... 23 
2.1 Study Rationale ............................................................................................................... 23 
2.2 Background ..................................................................................................................... 23 
2.2.1 
INDV-2000 ............................................................................................................. 23 
2.2.2 
Midazolam ............................................................................................................. 24 
2.3 Benefit/Risk Assessment ................................................................................................. 25 
2.3.1 
Risk Assessment .................................................................................................... 25 
2.3.2 
Benefit Assessment ............................................................................................... 26 
2.3.3 
Overall Benefit-risk Conclusion .............................................................................. 26 
3 OBJECTIVES AND ENDPOINTS ................................................................................................ 27 
4 STUDY DESIGN ....................................................................................................................... 28 
4.1 Overall Design ................................................................................................................. 28 
4.2 Scientific Rationale for Study Design ............................................................................... 29 
4.3 Justification for Dose ....................................................................................................... 29 
4.4 End of Study Definition ................................................................................................... 29 
4.5 Protocol Deviations ......................................................................................................... 30 
5 STUDY POPULATION .............................................................................................................. 31 
5.1 Inclusion Criteria ............................................................................................................. 31 
5.2 Exclusion Criteria ............................................................................................................. 31 
5.3 Lifestyle Considerations .................................................................................................. 33 
5.3.1 
Meals and Dietary Restrictions .............................................................................. 33 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................................................. 33 


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5.3.3 
Activity................................................................................................................... 34 
5.4 Screen Failures ................................................................................................................ 34 
5.5 Early Discontinuation ...................................................................................................... 34 
6 STUDY DRUG AND CONCOMITANT THERAPY ........................................................................ 35 
6.1 Study Drug(s) Administered ............................................................................................ 35 
6.2 Preparation, Handling, Storage, and Accountability ........................................................ 36 
6.2.1 
Drug Administration .............................................................................................. 36 
6.2.2 
Reporting Product Complaints .............................................................................. 37 
6.3 Assignment to Study Intervention ................................................................................... 37 
6.4 Blinding/Masking ............................................................................................................ 38 
6.5 Study Drug Compliance ................................................................................................... 38 
6.6 Dose Modification ........................................................................................................... 38 
6.7 Treatment Access to Study Drug After the End of the Study ........................................... 38 
6.8 Treatment of Study Drug Overdose ................................................................................. 38 
6.9 Prior and Concomitant Therapy ...................................................................................... 39 
6.9.1 
Rescue Medicine ................................................................................................... 39 
7 DISCONTINUATION OF STUDY DRUG, PARTICIPANT DISCONTINUATION/WITHDRAWAL AND 
STOPPING CRITERIA .................................................................................................................... 40 
7.1 Discontinuation of Study Drug and Study Stopping Criteria ............................................ 40 
7.1.1 
Liver Chemistry Stopping Criteria .......................................................................... 40 
7.1.2 
QTc Stopping Criteria ............................................................................................. 40 
7.2 Participant Discontinuation/Withdrawal From the Study ............................................... 40 
7.3 Lost to Follow-up ............................................................................................................. 41 
8 STUDY ASSESSMENTS AND PROCEDURES ............................................................................. 42 
8.1 Administrative Procedures .............................................................................................. 43 
8.1.1 
Informed Consent Procedure ................................................................................ 43 
8.1.2 
Inclusion and Exclusion Criteria ............................................................................. 43 
8.1.3 
Medical History/Demography ............................................................................... 43 
8.1.4 
Concomitant Medications ..................................................................................... 43 
8.1.5 
Check-in Criteria .................................................................................................... 43 
8.2 Efficacy and/or Immunogenicity Assessments ................................................................ 43 
8.3 Safety Assessments ......................................................................................................... 43 
8.3.1 
Physical Examinations ........................................................................................... 43 
8.3.2 
Vital Signs .............................................................................................................. 44 
8.3.3 
Electrocardiograms ................................................................................................ 44 


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8.3.4 
Pulse Oxymetry ..................................................................................................... 44 
8.3.5 
Clinical Safety Laboratory Tests ............................................................................. 45 
8.3.6 
Pregnancy Testing ................................................................................................. 45 
8.3.7 
Suicidal Ideation and Behaviour Risk Monitoring .................................................. 45 
8.3.8 
Sedation VAS ......................................................................................................... 46 
8.4 Adverse Events, Serious Adverse Events, and Other Safety Reporting ............................ 46 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ...................... 50 
8.4.2 
Method of Detecting AEs and SAEs ....................................................................... 50 
8.4.3 
Reporting and Follow-up of AEs and SAEs ............................................................. 50 
8.4.3.1 
Reporting of SAEs ............................................................................................................ 50 
8.4.3.2 
Recording and Follow-up of AE and/or SAE .................................................................... 51 
8.4.4 
Regulatory Reporting Requirements for SAEs ....................................................... 51 
8.4.5 
Pregnancy .............................................................................................................. 52 
8.5 Pharmacokinetics ............................................................................................................ 53 
8.6 Pharmacodynamics ......................................................................................................... 53 
8.7 Genetics .......................................................................................................................... 53 
8.8 Biomarkers ...................................................................................................................... 53 
8.9 Health Economics OR Medical Resource Utilisation and Health Economics .................... 53 
9 STATISTICAL CONSIDERATIONS ............................................................................................. 54 
9.1 Statistical Hypotheses ..................................................................................................... 54 
9.1.1 
Multiplicity Adjustment ......................................................................................... 54 
9.2 Analyses Sets ................................................................................................................... 54 
9.3 Statistical Analyses .......................................................................................................... 54 
9.3.1 
General Considerations ......................................................................................... 54 
9.3.2 
Primary Endpoints Analysis ................................................................................... 55 
9.3.3 
Secondary Endpoints Analysis ............................................................................... 55 
9.3.4 
Tertiary/Exploratory Endpoints Analysis ............................................................... 55 
9.4 Interim Analysis ............................................................................................................... 55 
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 


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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 
10.2 
Appendix 2: Clinical Laboratory Tests ....................................................................... 61 
10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy Information ....... 63 
10.3.1 Definitions ............................................................................................................. 63 
10.3.2 Contraception Guidance ........................................................................................ 63 
10.4 
Appendix 4: Liver Safety: Suggested Actions and Follow-up Assessments ................ 64 
10.5 
Appendix 5: Protocol Amendment History ................................................................ 66 
10.6 
Appendix 6: Pharmacokinetic Sampling Schedule ..................................................... 67 
10.7 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials .......................................................................................... 70 
10.8 
REFERENCES .............................................................................................................. 79 
 
TABLE OF TABLES 
Table 1 
Objectives and Endpoints .......................................................................................... 17 
Table 2 
Study Drugs Administered......................................................................................... 35 
Table 3 
Blood Volume during the Study ................................................................................ 42 
Table 4 
Populations for Analysis ............................................................................................ 54 
Table 5 
Protocol-required Safety Laboratory Tests ............................................................... 62 
Table 6 
PK sampling schedule ................................................................................................ 67 
Table 7 
List of Pharmacokinetic Parameters (non-exhaustive) .............................................. 68 
 
TABLE OF FIGURES 
Figure 1 
Study Schema ............................................................................................................ 19 
Figure 2 
Schedule of Events (SoE) ........................................................................................... 20 


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ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
aspartate aminotransferase 
AST 
alanine aminotransferase 
BID 
twice daily 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRF/eCRF 
Case Report Form/Electronic Case Report Form 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DORA 
dual orexin receptor antagonist 
ECG 
electrocardiogram 
EOS 
End of study 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practices 
GMR 
Geometric mean ratio 
HBsAg 
hepatitis B surface antigen 
HCl 
hydrochloride 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 


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IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M  
IND 
investigational new drug 
INR 
International normalised ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
 
 
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 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
WONCBP 
Women of nonchilbearing potential 
 


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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title:  
An Open Label, Fixed-sequence Study to Evaluate the Potential CYP3A4 Induction Effect of 
INDV-2000 using Oral Midazolam as a Probe in Healthy Adults Participants 
Short Title: 
Study of potential CYP3A4 induction by INDV-2000 in healthy adults  
Regulatory Agency Identifier Number(s): 
Registry 
Identifying Number 
IND 
145881 
Rationale:  


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Objectives and Endpoints 
Table 1 
Objectives and Endpoints 
Objective 
Endpoint 
Primary 
 
• To determine changes in primary 
pharmacokinetic (PK) parameters 
(maximal and overall plasma exposure) of 
midazolam and 1-hydroxymidazolam 
following repeated oral doses of 
INDV-2000 
• Cmax, AUC0-∞, and AUClast of midazolam and 
1-hydroxymidazolam following dosing of 
midazolam on Day 1 and dosing of 
midazolam + INDV-2000 on Day 15 
Secondary 
 
• To assess the safety and tolerability of 
repeated oral doses of INDV-2000 alone 
and in combination with midazolam as 
determined by adverse event (AE) 
reporting 
• Safety and tolerability of INDV-2000 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-centre, fixed-sequence study in healthy adult participants.  


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Brief Summary: 
The purpose of this study is to evaluate the CYP3A induction potential of INDV-2000 using 
midazolam as a sensitive substrate.  
Participants who meet the eligibility criteria will be admitted to the study site on Day -1, and 
will remain confined until after the 24-hour blood draw and/or study procedures on Day 16. 
On Day 1, participants will receive a single oral dose of midazolam syrup. On Days 2-15, 
participants will receive INDV-2000 BID with a single oral dose of midazolam syrup 
co-administered on Day 15.  
Participants who received all doses of study drugs will return to the study site 7±2 days after 
the last dose for end of study (EOS) procedures, and to determine if any AE has occurred since 
the last study visit. Participants who terminate the study early will be asked to complete EOS 
procedures at the time of early termination in place of an EOS visit. Participants will be 
encouraged to stay up to 24 hours after the last dose to complete early termination 
assessments. 
Number of Participants: 
Approximately 20 participants will be assigned to receive the study drugs. This sample size is 
based on earlier clinical experience and is expected to provide at least 16 evaluable 
participants,
 
  
Note: A participant will be considered enrolled at the time he/she receives the first dose of 
study drug. 
Study Treatment and Duration: 
On Day 1, participants will receive a single oral dose of 5 mg midazolam.  
On Days 2-15, participants will receive
 INDV-2000 BID (approximately 
every 12 hours) with a single oral dose of 5 mg midazolam co-administered with the morning 
INDV-2000 dose on Day 15. 
The total planned study duration (screening to EOS) for each participant will be approximately 
7 weeks. This includes a screening period of up to 4 weeks (ie within 28 days prior to dosing on 
Day 1), a treatment period of approximately 2 weeks (Days 1 to 16), and an EOS visit 
approximately 1 week from last dose (7±2 days).  
Data Monitoring/Other Committee: No 
 




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1.3 Schedule of Events (SoE) 
Figure 2 
Schedule of Events (SoE) 
Study Procedures 1 
Screening 2 
Treatment Period (Days) 
EOS/ET 
-1 3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examination including 
height and weight 5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 4 
Testicular examination 
(males only) 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 4 
COVID-19 screen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B, and 
Hepatitis C (antibody)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 4 
Serum pregnancy test 
(females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(females only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 4 
Serum FSH (PMP 
(females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology, serum 
chemistry 7, urinalysis 
X 
X 
 
X 8 
 
X 8 
 
 
 
X 8 
 
 
 
X 8 
 
 
X 8 
X 
X 4 
Coagulation 
X 
 
 
X 8 
 
 
 
 
 
X 8 
 
 
 
 
 
 
 
X 
X 4 
12-Lead ECG 
X 
 
X 9 
X 9 
X 9 
X 9 
X 9 
 
 
X 9 
X 9 
 
 
X 9 
X 9 
 
X 9 
X 
X 4 


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Study Procedures 1 
Screening 2 
Treatment Period (Days) 
EOS/ET 
-1 3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Vital signs 
X 
 
X 10 
X 10 
X 10 
X 10 
X 10 
 
 
X 10 
X 10 
 
 
X 10 
X 10 
 
X 10 
X 
X 4 
C-SSRS 11 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 4 
Sedation VAS 
 
 
X 12 
X 13 
 
X 13 
 
 
 
X 13 
 
 
 
X 13 
 
 
X 12 
X 
X 4 
Pulse oximetry 14 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
AE review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 4 
Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 4 
INDV-2000 dosing 15 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Midazolam dosing 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
PK Sampling 16 
 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
AE=adverse event; C-SSRS=Columbia suicide severity rating scale; COVID-19=Coronavirus disease 2019; ECG=electrocardiogram; ET=early termination; 
EOS=End of study; FSH=follicle stimulating hormone; HIV=Human immunodeficiency; PK=pharmacokinetic; PMP=postmenoposal; VAS=Visual Analogue Scale;  
 
1. For details on Procedures, refer to Section 8. 
2. Within 28 days before Day 1 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 
after the 24-hour blood draw and/or study procedures on Day 16. Participants may be admitted earlier than Day -1 for COVID-19 
testing not related to study protocol as per study site requirements.  
4. Participants who received all doses of study drugs will return to the study site 7±2 days after the last dose for EOS procedures, 
and to determine if any AE has occurred since the last study visit. Participants who terminate the study early will be asked to 
complete EOS procedures at the time of early termination in place of an EOS visit. Participants will be encouraged to stay up to 
24 hours after the last dose to complete early termination assessments. 
5. Height collected at screening only.  


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6. For male participants, a testicular/epididymal examination will be performed at screening, on Day 16, and at EOS Visit (7±2 days 
following last dosing) or early termination. Any clinically significant change from screening will be reported as an AE.  
7. 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.  
8. To be performed prior to morning dosing. 
9. On Days 1, 2, 4, 8, 12, and 15, 12-lead ECG will be collected within 2 hours prior to morning dose (predose) and at 1 hour 
(±20 min), 2 hours (±20 min), and 4 hours (±20 min) post morning dose; on Days 3, 5, 9, and 13, 12-lead ECG will be collected 
within 2 hours prior to morning dose (predose); on Day 16, the 12-lead ECG will be collected at 24 hours post Day 15 morning 
dose (±20 min).  
10. On Days 1, 2, 4, 8, 12, and 15, vital signs will be collected within 2 hours prior to morning dose (predose) and at 1 hour (±15 min), 
2 hours (±15 min), and 4 hours (±15 min) post morning dose; on Days 3, 5, 9, and 13, vital signs will be collected within 2 hours 
prior to morning dose (predose); on Day 16, the vital signs will be collected at 24 hours post Day 15 morning dose (±20 min). 
11. Baseline/Screening C-SSRS version (lifetime history and past 6 months) will be completed at screening, the Since last Visit C-SSRS 
version will be completed at all other time points. On Day 8 and Day 15, C-SSRS will be collected at 6 hours (±1 hour) post 
morning dose. 
12. Sedation VAS will be collected within 1 hour prior to morning dosing (predose) and at 30 min (±5 min), 1 hour (±10 min) and 
2 hours (±10 min) post morning dose.  
13. Sedation VAS will be collected within 1 hour prior to morning dosing (predose) and at 2 hours (±10 min) post morning dose. 
14. Baseline pulse oximetry will be performed within 1 hour prior to morning dosing; pulse oximetry will be monitored continuously 
with a pulse oximeter for approximately 6 hours post-dose, with readings recorded 2 hours, 4 hours, and 6 hours post-dose 
(±10 min). 
15. INDV-2000 will be administered BID (ie, approximately every 12 hours). 
16. For PK collection time points, please refer to Section 10.6 (appendix). 


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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 
2.2 Background 
2.2.1 INDV-2000 
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 nonclinical 
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) and 
dual OX1R/OX2R antagonists already in clinical development. BELSOMRA® (suvorexant) and 
DAYVIGO® (lemborexant) are dual OX1R/OX2R antagonists approved for the treatment of 
insomnia (Coleman 2017, Murphy 2017). 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 Investigator’s Brochure (IB) and IB supplement.  




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oral doses of 0.25 to 1 mg/kg. Midazolam is primarily metabolised in the gut and liver by 
CYP3A4 to its pharmacologic active metabolite, 1-hydroxymidazolam, followed by 
glucuronidation. The active metabolite, 1-hydroxymidazolam, is equipotent and equally 
effective as unchanged midazolam on a total plasma concentration basis. Midazolam is also 
metabolised to 2 other minor metabolites (about 4% of the dose). The mean elimination T1/2 of 
midazolam ranges from 2.2 to 6.8 hours. After oral or intravenous (IV) administration, 63% to 
80% of midazolam is recovered in urine as 1-hydroxymidazolam glucuronide. 
The most frequently reported AEs following midazolam administration include emesis (8%) and 
nausea (4%). Midazolam HCl syrup has also been associated with reports of respiratory 
depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used 
concomitantly with other CNS depressants.  
Refer to the full prescribing information for a more detailed background on midazolam 
(Midazolam HCl Syrup, 2021). 
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 and 
midazolam may be found in the IB and IB supplement and in the prescribing information 
(Midazolam HCl Syrup, 2021), respectively. 
2.3.1 Risk Assessment 
Investigational Study Drug:  


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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. 
Other Study Medication (Midazolam):  
Midazolam is associated with reports of respiratory depression, airway obstruction, 
desaturation, hypoxia, and apnea, although most often when used concomitantly with other 
CNS depressants. An oral dose of midazolam (0.1 mg/kg) affects peak saccadic velocity of eye 
movement, postural sway area, critical flicker fusion frequency, and mental sedation as 
measured on a VAS (Misaka 2011). To minimise the risk of AE occurrence, a lower dose (5 mg) 
than that typically required for effective sedation (0.5 mg/kg to a maximum dose of 20 mg) 
according to the dosing recommendations found in the full prescribing information for 
midazolam will be administered to ensure a safety margin while allowing robust PK assessment. 
In addition, as both study drugs may induce somnolence, mental sedation as measured on a 
VAS will be evaluated throughout the study. Also, oxygen level (oxygen saturation) in the blood 
will be measured via pulse oximetry in every participants for the 6 hours following each 
midazolam dosing.  
Rescue medication will also be available as needed. 
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. 
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 
 BID for 14 days is not expected to cause any safety concern in healthy 
participants. The dose of midazolam administered in this study is also not anticipated to induce 
any potential risk to participants taking part in this study, as it is a single dose administered at a 
lower dose than typically required for effective sedation according to the dosing 
recommendations found in the full prescribing information for midazolam. 
The study site will follow coronavirus plan to minimise the exposure of participants to 
coronavirus disease 2019 (COVID-19). The Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) approved COVID-19 clinical pharmacology unit management plan will be 
provided separately.  
The safety monitoring practices employed by this protocol (ie, AEs, clinical laboratory tests, vital 
sign measurements, pulse oximetry, 12-lead ECG, sedation VAS, C-SSRS, and physical 
examination) are adequate to protect the participants’ safety and should detect all expected 
TEAEs. 


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3 OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Primary 
 
• To determine changes in primary PK 
parameters (maximal and overall plasma 
exposure) of midazolam and 
1-hydroxymidazolam following repeated 
oral doses of INDV-2000 
• Cmax, AUC0-∞, and AUClast of midazolam 
and 1-hydroxymidazolam following 
dosing of midazolam on Day 1 and dosing 
of midazolam + INDV-2000 on Day 15 
Secondary 
 
• To assess the safety and tolerability of 
repeated oral doses of INDV-2000 alone 
and in combination with midazolam as 
determined by AE reporting 
• Safety and tolerability of INDV-2000 as 
determined by AE reporting (incidence, 
seriousness, severity, and relatedness of 
TEAEs) 
Tertiary/Exploratory 
 


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4 STUDY DESIGN 
4.1 Overall Design 
• 
This is an open label, single-centre, fixed-sequence study in healthy adult 
participants. 
• 
Approximately 20 males and females of non-child bearing potential participants will 
be enrolled to provide at least 16 evaluable participants. 
• 
The total planned study duration (screening to EOS) for each participant is 
approximately 7 weeks. This includes a screening period, a treatment period, and an 
EOS visit: 
o Screening: Day -28 up to dosing on Day 1; 
o Treatment Period: Day 1 to Day 16 
 Day -1: Check-in at the time indicated by the study site, for eligible 
participants. Participants may be admitted earlier than Day -1 for 
COVID-19 testing not related to study protocol as per study site 
requirements. 
 Day 1: Participants will receive a single oral dose of midazolam. 
 Days 2 to 15: Participants will receive oral doses of INDV-2000 BID. 
 Day 15: Participants will receive a single oral dose of midazolam 
co-administered with INDV-2000 morning dose. 
 Day 16: Check-out from the study site following completion of the 
24-hour blood draw and/or study procedures scheduled on that day; 
note that the study site may decide to confine the participants for longer 
periods at the Investigator’s discretion. 
o EOS Visit: Participants who received all doses of study drugs will return to the 
study site 7±2 days after the last dose for EOS procedures, and to determine if 
any AE has occurred since the last study visit. Participants who terminate the 
study early will be asked to complete EOS procedures at the time of early 
termination in place of an EOS visit and will be encouraged to stay up to 24 hours 
after the last dose to complete early termination assessments. 
• 
Blood sampling for midazolam and 1-hydroxymidazolam plasma concentrations will 
be conducted for 24 hours on Day 1 and Day 15. 
• 
Safety will be monitored throughout the study by AE review, clinical laboratory tests, 
vital sign measurements, pulse oximetry, ECG parameters, C-SSRS, sedation VAS, and 
physical examination. 


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4.2 Scientific Rationale for Study Design 
This clinical study will evaluate the potential effect of INDV-2000 on the activity of CYP3A, 
thereby providing information on whether CYP3A substrate drugs can be co-administered safely 
with INDV-2000, and if there is a need for focused clinical DDI studies (eg, oral contraceptive 
studies). Midazolam is considered a sensitive index substrate of CYP3A4 as per the Food and 
Drug Administration’s (FDA’s) web site for Drug Development and Drug Interactions (FDA 2022) 
and was thus selected as a probe for this study. Although the syrup formulation is indicated for 
use in paediatric patients, it was selected over the IV formulation as it allows to assess the 
intestinal CYP3A activity and is routinely used in the adult population and commonly selected 
for DDI studies.  
The study is designed as an open label, fixed-sequence study for the following reasons: 
• 
Since the primary endpoint is an objective measurement, there is no risk of potential 
bias of the study results; hence, neither study blinding nor inclusion of a placebo 
group is required, and the study can be conducted as open label. 
• 
A fixed-sequence allows to prevent any carryover effect of INDV-2000 on CYP3A 
activity due to INDV-2000 potential inductive effect while providing the advantage of 
reducing the study variability since participants act as their own control. 
Since the purpose of the study is to validate the potential of INDV-2000 to perpetrate induction, 
and as it may take about 2 weeks of daily administration to achieve maximum level of induction 
for a perpetrator, INDV-2000 will be administered for 14 days (Day 2 to Day 15) with the 
substrate being co-administered on Day 15. 
Oral administration of midazolam has demonstrated linear PK and thus will be given as a single 
dose. 
Based on the short half-life of midazolam and 1-hydroxymidazolam, PK sampling for a duration 
of 24 hours should be adequate to ensure robust characterization of total exposure of the 
analytes. Blood samples for INDV-2000 will be collected to confirm expected plasma 
concentrations.  
4.3 Justification for Dose 
4.4 End of Study Definition 
The end of the study is defined as the EOS visit (Day 22±2 days).  
A participant is considered to have completed the study if the participant has completed 
dosing, did not discontinue or terminate the study early, and has completed most of the 
scheduled procedures including the EOS visit (Day 22±2 day). 


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4.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or ICH/GCP 
requirements. The noncompliance may be either on the part of the 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 18 to 55 years of age inclusive, at the time of signing the 
informed consent. 
2. 
Body weight of a minimum of 50.0 kg at the Screening Visit and body mass index 
within the range 18.0 – 32.0 kg/m2 (inclusive). 
3. 
Male or female who is healthy as determined by medical evaluation.  
4. 
Females will be of non-childbearing potential. Females of non-childbearing potential 
are considered women who: 
• Do not have a uterus, or 
• Are surgically sterile (eg, has undergone complete hysterectomy, bilateral 
oophorectomy, hysteroscopic sterilization, or tubal ligation), or 
• Have permanent cessation of ovarian function due to ovarian failure or surgical 
removal of the ovaries, or 
• Are post-menopausal as defined by 12 months or more of spontaneous 
amenorrhea as confirmed by a follicle-stimulating hormone (FSH) >30 mIU/mL 
5. 
Male participants agree to follow contraception guidelines in Section 10.3 
(appendix). 
6. 
Continuous non-smoker who has not used nicotine- and tobacco-containing 
products for at least 3 months prior to the first dosing based on participant 
self-reporting. 
7. 
Capable of giving signed informed consent as described in Section 10.1.3 (appendix) 
which includes compliance with the requirements and restrictions listed in the 
Informed Consent Form (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 GI 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. 


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5. 
Current active hepatic or biliary disease.  
6. 
Participants with cholecystectomy <90 days prior to screening. 
7. 
Positive test results for human immunodeficiency virus (HIV)-1/HIV-2 antibodies, 
Hepatitis B surface antigen (HBsAg) or Hepatitis C antibodies. 
8. 
Have a blood pressure reading outside of the following range: Systolic <86 or 
>149 mmHg; Diastolic <50 or >94 mmHg 
9. 
Serious cardiac illness or other medical condition including, but not limited to: 
• 
Uncontrolled arrhythmias 
• 
History of congestive heart failure  
• 
QTcF >450 msec for males and >470 msec for females 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, hormone replacement therapy, 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 first dose 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 first dose of 
study drug.  
13. 
Any consumption of food or drink containing poppy seeds, grapefruit or Seville 
oranges within 14 days prior to the first dose of study drug. 
14. 
Regular alcohol consumption in males >21 units per week and females >14 units per 
week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine). 
15. 
Positive test result for alcohol and/or drugs of abuse at screening or at check-in. 
16. 
Female participant with a positive pregnancy test at the Screening Visit or at first 
check-in or who are lactating. 
17. 
Concurrent treatment or treatment with an investigational drug or device within 
30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug. 
18. 
Blood donation of approximately 500 mL or more within 56 days or plasma donation 
within 7 days of screening. 
19. 
Known hypersensitivity to INDV-2000 or any other ingredient in the INDV-2000 
formulation. 


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20. 
Known hypersensitivity to midazolam or any other ingredient in midazolam HCl 
syrup. 
21. 
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. 
22. 
Major surgical procedure (as defined by the Investigator) within 90 days prior to the 
first dose of study drug or still recovering from prior surgery. 
23. 
Concurrent enrolment in another clinical study, unless it is an observational study. 
24. 
Participants who are unable, in the opinion of the Investigator, to comply fully with 
the study requirements. 
25. 
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 each dosing of study drug, but will be allowed ad libitum at all 
other times. 
2. 
On all PK days (Day 1 and Day 15), participants will fast overnight for at least 
10 hours before and at least 4 hours after each morning dose of study drug. For all 
other dosing, participants will fast for at least 2 hour before and at least 2 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 the first 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). 
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, and chocolate) for 24 hours prior to 
the first dose 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 


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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 the first 
dose 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 the first dosing and through confinement. 
5.3.3 Activity 
1. 
Participants will remain seated for the first 4 hours post morning dose and the first 
2 hours post evening dose, except when they are supine or semi reclined for study 
procedures. Participants will then resume normal activity. During the first 4 hours 
post morning dose or 2 hours post evening dose, participants may be allowed to rise 
for brief periods under supervision (eg, in order to use the toilet facilities). 
2. 
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.  
3. 
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 
See Section 9.2 for definition of enrolled participant. 
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 screen failure 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 Early Discontinuation  
A participant will be considered an early discontinuer if the participant received study drug and 
did not complete all visits. Reasons for not completing all visits will be captured in the 
participant source documents and the Case Report Form (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. 
6.1 Study Drug(s) Administered 
 
Table 2 
Study Drugs Administered 
Drug Name 
INDV-2000  
Midazolam HCl 


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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 all study drug received and any discrepancies are 
reported and resolved before use of the study drug 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. 
All 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 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 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 study drugs are 
provided in the pharmacy manual. 
8. 
Upon completion of the study and/or as requested by Indivior, copies of study drug 
accountability records will be provided to Indivior or designee. 
6.2.1 Drug Administration 
When participants are dosed at the site, they will receive the study drug(s) directly from the 
Investigator or designee, under medical supervision. 
A record of the number of INDV-2000 capsules 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 Midazolam 5 mg (2.5 mL of 2 mg/mL syrup) on Day 1 
o INDV-2000
 BID on Day 2 to Day 15 with midazolam 
5 mg (2.5 mL of 2 mg/mL syrup) co-administered on the morning of Day 15 


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• Following initial INDV-2000 morning dosing on Day 2, each subsequent INDV-2000 
morning dose will be administered within 1 hour before or after the dosing time 
established on Day 2. For each evening dose, INDV-2000 will be administered 
approximately 12 hours after the morning dose on that day. 
• 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). 
• Participants will be instructed not to crush, split, or chew the capsules. 
• 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 the 
study drug and includes, but is not limited to broken capsules, labelling defects, packaging 
defects, 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 


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will be assigned a unique identification number at the time of the first dosing, different from 
the screening number, and will receive the corresponding product.  
All participants will receive each treatment in a sequential manner.  
6.4 Blinding/Masking 
This is an open label study. There is no randomization in this study. 
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. Participants’ hands will also be verified to ensure that the study drug was 
ingested.  
Any deviation(s) from the prescribed dosage regimen will be recorded in the electronic (e)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 and hands. 
The exact clock time of dosing will be recorded. 
6.6 Dose Modification 
The dose and administration of the study drugs 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 INDV-2000 or midazolam and 1-hydroxymidazolam) for PK 
analysis within 24 hours from the time of the last dose 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. 


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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 
• 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 investigational 
drug or device within 5 half-lives (if known) of the investigational agent or 30 days prior to the 
first dose 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 first dose of study drug 
until completion of the 7±2 days EOS Visit. Hormone replacement therapy and thyroid hormone 
replacement therapy, if the participant has been on the same stable dose for at least 3 months 
prior to the first dosing, will also be allowed. After first dosing of study drug, acetaminophen, at 
doses of up to 2 grams/24 hours, is permitted for use 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 first dose of study drug until completion of the 7±2 days EOS 
Visit. Appropriate sources (eg, Flockhart Table™) will be consulted to confirm lack of 
PK/pharmacodynamic interaction with the study drug(s). 
6.9.1 Rescue Medicine 
For severe AEs, including any midazolam-related events such as respiratory depression and 
oxygen desaturation, standard contents of the emergency crash cart available at the study site 
(eg, oxygen, flumazenil) will be used as rescue medication at the discretion of the Investigator 
or designee. 


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7 DISCONTINUATION OF STUDY DRUG, PARTICIPANT 
DISCONTINUATION/WITHDRAWAL AND STOPPING CRITERIA 
7.1 Discontinuation of Study Drug and Study Stopping Criteria 
7.1.1 Liver Chemistry Stopping Criteria 
7.1.2 QTc Stopping Criteria 


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7.3 Lost to Follow-up 
An enrolled participant who has received study drug will be considered lost to follow-up if he or 
she 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. 
• 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.  


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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. 
• The blood collections for midazolam and 1-hydroxymidazolam are the critical 
parameters and need to be done 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 
nonscheduled 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 
Sample Type 
Number 
of Time 
Points 
Approximate 
Volume per Time 
Point * (mL) 
Approximate Sample 
Volume Over Course 
of Study (mL) 
Screening laboratory safety tests 
(including haematology, serum chemistry, 
serology, and coagulation), FSH (for PMP 
female participants only) and serum 
pregnancy (for female participants only). 
1 
16 
16 
On-study haematology, serum chemistry 
8 
12.5 
100 
On-study coagulation (prothrombin 
time/International normalised ratio [INR] 
and activated partial thromboplastin 
time) 
4 
3.5 
14 
Blood for Midazolam and 
1-hydroxymidazolam PK 
32 
4 
128 
Total Blood Volume (mL)→ 
294 ** 
* 
Represents the largest collection tube that is expected to be used (a smaller tube may be used). 
** If additional safety or PK analysis are necessary, additional blood may be obtained (up to a maximum of 50 mL).  


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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.  
• Female participants must have a negative urine pregnancy test. 
• Participants must have a negative result obtained from the urine drug screen and 
the alcohol test. 
• Participants must have a negative polymerase chain reaction test result for 
COVID-19. 
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. 
8.3.1 Physical Examinations 
• Physical examination will be conducted as outlined in the SoE (Section 1.3). 
• Male participants will undergo a testicular exam as outlined in the SoE (Section 1.3). 


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• 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 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 morning 
dosing for the pre-dose morning 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 morning 
dosing. When scheduled post-dose, ECGs will be performed within approximately 
20 minutes of the scheduled time point. 
8.3.4 Pulse Oxymetry 
• Pulse oximetry reading will be collected using a pulse oximeter (oxygen levels as 
saturation [%]) as outlined in the SoE (Section 1.3). 
• Where the time of reading coincides with a blood sampling time point, the reading will 
be collected within approximately 10 minutes prior to the scheduled time point. 
Readings may be taken at other times, if deemed necessary by the Investigator or 
designee. 
• Any oxygen saturation reading deemed clinically significant by the Investigator will be 
documented as an AE. 


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8.3.5 Clinical Safety Laboratory Tests 
• See Section 10.2 (appendix) for the list of clinical laboratory tests to be performed and 
to the SoE (Section 1.3) for the timing and frequency. 
• 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), 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.  
8.3.6 Pregnancy Testing 
• Pregnancy testing will be conducted at as outlined in the SoE (Section 1.3). 
• In the case where a participant’s routine pregnancy test as required per protocol is 
positive for pregnancy prior to dosing, the participant should not be dosed. If the 
participant has a positive urine pregnancy test, a confirmatory serum pregnancy test 
should be performed. 
• Additional pregnancy tests may be performed, as determined necessary by the 
Investigator or required by local regulation, to establish the absence of pregnancy at any 
time during the study. 
8.3.7 Suicidal Ideation and Behaviour Risk Monitoring 
• The C-SSRS is a questionnaire scale to detect emergent suicide symptoms (suicidal 
ideation or actual suicidal behaviour). Baseline evaluations will assess the lifetime 
experience of the participant with suicidal ideation and behaviour and post baseline 
evaluations will focus on suicidality since the last study visit. 
• C-SSRS questionnaire will be conducted as outlined in the SoE (Section 1.3); the 
Baseline/Screening C-SSRS version will be completed at screening (lifetime history and 


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past 6 months) and the Since Last Visit C-SSRS version will be completed at all other 
time points. 
• On Day 8 and Day 15, C-SSRS will be conducted within 1 hour of the scheduled time 
point.  
• Additional C-SSRS assessment may be performed at other times if deemed necessary by 
the Investigator or designee.  
• The C-SSRS is to be administered at the site by an appropriately qualified/trained 
individual and a copy of the questionnaire to be used will be kept in the study binder. In 
addition, participants who at any time during this study spontaneously report AEs of 
suicidal ideation or suicidal behaviour must be assessed by the Investigator or designee 
and referred for further mental health evaluation as clinically indicated. 
8.3.8 Sedation VAS 
• VAS will be conducted as outlined in the SoE (Section 1.3)  
• When scheduled pre-dose, VAS will be measured within 1 hour prior to morning dosing. 
When scheduled post-dose, VAS will be performed within approximately 5 minutes for 
the 30-minute scheduled time point and within 10 minutes for the 1-hour and 2-hour 
scheduled time points. 
• The VAS to be used will be provided in a separate document. 
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 discontinue the study drug (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). 


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• 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 DDI 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). 
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, 


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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 alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) ≥3 × upper limit of normal (ULN) and bilirubin 
≥2 × ULN (>35% direct). 
Definition of SUSAR 
A suspected unexpected serious adverse reaction (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 10.7). Any event not falling under one of the specific categories 
listed will be graded as a “Systemic Illness”. 


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For events that occur after first study drug administration, 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.  
• 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. 


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8.4.1 Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from ICF signature until the EOS Visit on Day 22 (±2 days) or at 
early termination. Any ongoing AEs at the time of the EOS Visit (ie, Day 22 [±2 days]) or at early 
termination will be appropriately followed-up until resolution or 14 days after the EOS Visit 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. 
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 
nonleading 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. 


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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 eCRF.  
• 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. 
• 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. 


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• 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 participants and in female partners of male 
participants will be collected after the first study drug administration and until 90 days 
following the last dose.  
• 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 
participants and in 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 (either through maternal exposure or 
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 participants and in 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 participants and in 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 former female 
participants and in female partners of male participants, he or she may learn of an SAE 
through spontaneous reporting. 


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• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
8.5 Pharmacokinetics 
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 Health Economics OR Medical Resource Utilisation and Health Economics 
Health economics OR 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.  
The primary objective of the study is to determine changes in primary PK parameters of 
midazolam and 1-hydroxymidazolam. These changes will be estimated by calculating the 
geometric mean ratio (GMR) of each primary PK parameter with and without INDV-2000, where 
“with” is considered the test treatment and “without” is considered the reference. Ninety 
(90)% confidence intervals for the GMRs will be calculated. 
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 at least one dose of study drug and have 
an adequate number of PK samples collected to derive any PK 
parameter, and have no protocol deviations that would 
significantly alter plasma concentrations of study drugs. All 
available data will be included in the concentration and PK 
parameter tables to the extent possible. Data for each 
participant will be included in the summary statistics and 
statistical comparisons of PK parameters.  
Safety Analysis Set 
All participants who receive at least 1 dose of study drug.  
 
9.3 Statistical Analyses 
9.3.1 General Considerations 
The statistical analysis plan (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. The 
SAP will be prepared by Indivior. This section is a summary of the planned statistical analyses of 
the most important endpoints including primary and secondary endpoints. 


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9.3.2 Primary Endpoints Analysis 
For both midazolam and 1-hydroxymidazolam, Cmax, AUC0-∞, and AUClast in the presence (Day 15) 
of INDV-2000 will be compared to Cmax, AUC0-∞, and AUClast, respectively, in the absence (Day 1) 
of INDV-2000 using GMRs and 90% CIs calculated using random effects models. The primary 
endpoints will be analysed using the PK Analysis Set. Details on the statistical analyses will be 
included in the SAP. 
9.3.3 Secondary Endpoints Analysis 
TEAEs will be defined as AEs that start on or after the first dose 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/Exploratory Endpoints Analysis 
9.4 Interim Analysis 
No interim analysis is planned. 
9.5 Sample Size Determination 
Approximately 20 participants will be assigned to receive study drug. This sample size is based 
on earlier clinical experience and is expected to provide at least 16 evaluable participants, 
defined as participants with plasma concentration-time profiles sufficient for calculation of PK 
parameters during the study.  
 


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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 Code of Federal Regulations (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 
• All participant data relating to the study will be recorded on printed or CRFs unless 
transmitted to Indivior or designee electronically (eg, laboratory data). 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 noncompliance 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 eCRF 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. 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 
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. 


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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. 
 


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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.  
• Pregnancy testing: Female participants should only be enrolled after a negative serum 
pregnancy test result at screening and a negative urine pregnancy test result at 
check-in. Additional pregnancy testing will be performed as specified in the SoE 
(Section 1.3) and as deemed necessary by the Investigator or required by local 
regulation, to establish the absence of pregnancy at any time during the study. 


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Table 5 
Protocol-required Safety Laboratory Tests 
Haematology 
 
Serum Chemistry * 
• 
Haemoglobin 
• 
Haematocrit  
• 
Total and differential leukocyte count 
• 
Red blood cell count 
• 
Platelet count 
 
Coagulation 
• 
Prothrombin time/INR 
• 
Activated partial thromboplastin 
 
 
• 
Blood Urea Nitrogen 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase (ALP) 
• 
AST 
• 
ALT 
• 
Gamma-glutamyl Transferase 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Glucose (fasting) 
• 
Creatinine ** 
• 
Total protein  
• 
Total cholesterol  
• 
Triglycerides  
• 
Creatine phosphokinase 
 
Urinalysis 
 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Protein *** 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood *** 
• 
Nitrite*** 
• 
Urobilinogen 
• 
Leukocyte esterase *** 
 
• 
HIV-1; HIV-2 (screening only) 
• 
HBsAg (screening only) 
• 
HCV antibodies (screening only) 
• 
Urine drug screen 
 
Opiates § 
 
Opioids 
 
Amphetamines 
 
Barbiturates 
 
Benzodiazepines 
 
Cocaine 
 
Cannabinoids 
 
Fentanyl  
 
Oxycodone  
• 
Urine alcohol screen 
• 
Serum pregnancy test (for females only; screening 
only) 
• 
Urine pregnancy test (for females only) 
• 
FSH (for PMP females only; screening only) 
• 
COVID-19 PCR (check-in only) 
 
* 
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. 
** At the Screening Visit, creatinine clearance will be calculated using the Cockcroft-Gault formula. 
*** If urinalysis is abnormal for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
 


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10.3 Appendix 3: Contraceptive Guidance and Collection of Pregnancy Information 
10.3.1 Definitions 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
• Do not have a uterus, or 
• Are surgically sterile (eg, has undergone complete hysterectomy, bilateral 
oophorectomy, hysteroscopic sterilization, or tubal ligation), or 
• Have permanent cessation of ovarian function due to ovarian failure or surgical removal 
of the ovaries, or 
• Are post-menopausal as defined by 12 months or more of spontaneous amenorrhea as 
confirmed by a FSH >30 mIH/mL. 
10.3.2 Contraception Guidance 
Female Participants 
No contraception methods are required as females of childbearing potential will not be eligible 
to enroll in the study. Only females of non-childbearing potential will be enrolled. 
Male Participants 
Male participants with female partners of childbearing potential must comply with the 
following contraception requirements from the time of first dose of study medication until at 
least 90 days after the last dose of study medication.  
• All non-sterile male participants must use highly effective contraception from first study 
drug administration through 90 days after their last study drug administration if sexually 
active with a non-pregnant partner of child bearing potential. Highly effective 
contraception is defined as:  
o 
True sexual abstinence  
o 
Condom plus partner’s use of:  
 
Oral, intravaginal, injectables, implants, or transdermal combined 
(estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation  
 
Intrauterine device  
 
Intrauterine hormone-releasing system  
 
Bilateral tubal occlusion 
• No restrictions are required for a vasectomised male provided his vasectomy has been 
performed 4 months or more prior to the first dosing. A male who has been 
vasectomised less than 4 months prior to the first dosing must follow the same 
restrictions as a non-vasectomised male. 
Male participant must agree not to donate sperm from the first dosing until at least 90 days 
after the last dosing. 
 


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10.4 Appendix 4: Liver Safety: Suggested Actions and Follow-up Assessments  
The following should occur if a participant meets any of the liver chemistry stopping criteria as 
outlined below: 
Phase I liver chemistry stopping criteria are designed to assure participant safety and to 
evaluate liver event etiology. 
Phase I Liver Chemistry Stopping Criteria and Follow-Up Assessments 


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References 
EASL Clinical Practice Guidelines: Drug-induced liver injury. J of Hepatol. 2019; 70 (6):1222-61. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and 
Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-84. 
 


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10.5 Appendix 5: Protocol Amendment History 
Protocol modifications, except those intended to reduce immediate risk to study participants, 
may be made only by Indivior. A protocol change intended to eliminate an apparent immediate 
hazard to participants may be implemented immediately, provided the IRB/IEC is notified 
within 5 days. 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
 


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10.6 Appendix 6: Pharmacokinetic Sampling Schedule 


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Table 7 
List of Pharmacokinetic Parameters (non-exhaustive) 


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10.7 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 subjects. 
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 
the choice of values in the toxicity table. For example, additional parameters might be added 


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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 
* Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when characterising bradycardia 
among some healthy subject populations, for example, conditioned athletes. 


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10 Apr 2023 
 
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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 
>800gms/24 
hours or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non- narcotic pain 
reliever >24 hours or 
some 
interference 
with activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents 
daily activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents 
daily activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents 
daily 
activity 
ER visit or 
hospitalization 
 
Systemic Illness 
Mild (Grade 1) 
Moderate(Grade 2) 
Severe (Grade 3) 
Potentially Life-
Threatening 
(Grade 4) 
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations) 
No interference 
with activity 
Some 
interference with 
activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires 
medical 
intervention 
ER visit or 
hospitalization 


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10 Apr 2023 
 
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Page 76 of 80 
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  
I n di vi or 
Cli nic al St u dy Pr ot oc ol: I N D V-2 0 0 0 -1 0 4 Fi n al, A m e n d m e nt 1  
1 0 A pr 2 0 2 3  
 
C o nfi d e nti al  
P a g e 7 7  of 8 0 
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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10 Apr 2023 
 
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Page 78 of 80 
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 Apr 2023 
 
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10.8 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. 
 
Berger B, Kaufmann P, Koch A, Dingemanse J. Impact of the Selective Orexin‐1 Receptor 
Antagonist ACT‐539313 on the Pharmacokinetics of the CYP3A Probe Drug Midazolam in 
Healthy Male Subjects. The Journal of Clinical Pharmacology. 2020;60(7):931-41.  
 
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: 15 
December 2022. 
 
Food and Drug Administration: Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors, and Inducers. Available from: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteract
ionslabeling/ucm093664.htm. (2022). Accessed on: 15 December 2022. 
 
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. 
 
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. 
 
Midazolam hydrochloride (Padagis US, LLC), syrup, full prescribing information (electronic 
monograph; document revised: Aug 2022). Available from: 
https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0be63f63-6a93-4782-8f9c-
d13ca5ae44bd. Accessed on: 15 December 2022. 
 


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Misaka S, Kurosawa S, Uchida S, Yoshida A, Kato Y, Kagawa Y, Yamada S. Evaluation of the 
pharmacokinetic interaction of midazolam with ursodeoxycholic acid, ketoconazole and 
dexamethasone by brain benzodiazepine receptor occupancy. J Pharm Pharmacol. 
2011;63(1):58-64.  
 
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  
 
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. 
 
Zhou D, Sunzel M, Ribadeneira MD, Smith MA, Desai D, Lin J, Grimm SW. A clinical study to 
assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABAA receptor modulator –an 
in vitro and in vivo comparison. British Journal of Clinical Pharmacology. 2012;74(1):98-108. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN: INDV-2000-104 
Protocol Title:  An Open Label, Fixed-sequence Study 
to Evaluate the Potential CYP3A4 Induction Effect of 
INDV-2000 using Oral Midazolam as a Probe in Healthy 
Adults Participants 
Final Version: 22 May 2023
NCT: NCT05694533 


 
 
 
SAP for Protocol INDV-2000-104 
INDV-2000 
Statistical Analysis Plan 
 
Protocol Title:  
An Open Label, Fixed-sequence Study to Evaluate the 
Potential CYP3A4 Induction Effect of INDV-2000 using Oral 
Midazolam as a Probe in Healthy Adults Participants 
Protocol Number:    
INDV-2000-104 
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: 
 
Amendment 1 
Date:  
 
 
10 Apr 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-2000-104 
INDV-2000 
 
Statistical Analysis Plan Approval  


 
 
 
SAP for Protocol INDV-2000-104 
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 ..............................................................................................11 
5.1. General Considerations .....................................................................................................11 
5.1.1. Timing of Analyses ..................................................................................................11 
5.1.2. Programming Environment ......................................................................................12 
5.1.3. Reporting Conventions ............................................................................................12 
5.1.4. General Analysis Conventions .................................................................................12 
5.1.5. Definitions................................................................................................................12 
5.2. Study Conduct and Participant Disposition ......................................................................13 
5.3. Primary Endpoints Analysis .............................................................................................13 
5.3.1. Definition of Endpoints............................................................................................13 
5.3.2. Main Analytical Approach .......................................................................................14 
5.4. Secondary Endpoints Analysis .........................................................................................15 
5.4.1. Definition of Endpoints............................................................................................15 
5.4.2. Main Analytical Approach .......................................................................................15 
5.5. Exploratory Endpoints Analysis .......................................................................................15 
5.5.1. Definition of Endpoints............................................................................................15 
5.5.2. Main Analytical Approach .......................................................................................15 
5.6. Other Safety Analyses.......................................................................................................16 
5.6.1. Study Drug Exposure ...............................................................................................16 
5.6.2. Adverse Events ........................................................................................................16 
5.6.3. Additional Safety Assessments ................................................................................17 


 
 
 
SAP for Protocol INDV-2000-104 
INDV-2000 
5.6.3.1. Laboratory Data ..............................................................................................17 
5.6.3.2. Vital Signs .......................................................................................................19 
5.6.3.3. Electrocardiogram (ECG) Data .......................................................................19 
5.6.3.4. Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................19 
5.7. Other Analyses ..................................................................................................................20 
5.7.1. Demographic and Baseline Characteristics .............................................................20 
5.7.2. Medical History .......................................................................................................20 
5.7.3. Prior and Concomitant Medications and Therapies .................................................20 
5.7.4. Protocol Deviations ..................................................................................................20 
5.8. Interim Analyses ...............................................................................................................20 
6. SUPPORTING DOCUMENTATION .................................................................................21 
6.1. Appendix 1: List of Abbreviations ...................................................................................22 
6.2. Appendix 2: Changes to Protocol-Planned Analyses .......................................................22 
6.3. Appendix 3: Definition and Use of Visit Windows in Reporting .....................................22 
6.4. Appendix 4: Endpoint Derivations ...................................................................................23 
6.4.1. Pharmacokinetic Endpoints .....................................................................................23 
6.5. Appendix 5: Statistical Methodology Details ...................................................................23 
6.5.1.1. Concentration ..................................................................................................23 
6.5.1.2. Plasma PK Parameters ....................................................................................24 
6.6. Appendix 6: Methods to Manage Missing Data ...............................................................24 
6.6.1. BLQ PK Concentrations ..........................................................................................24 
6.6.2. AEs ...........................................................................................................................24 
6.6.3. Medications and Therapies ......................................................................................25 
6.7. Appendix 7: Data Set Descriptions ...................................................................................26 
7. REFERENCES ....................................................................................................................27 
 
 
 
 
 
 
 


 
 
 
SAP for Protocol INDV-2000-104 
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 ...............................................................18 
 
LIST OF FIGURES 
Figure 1. 
Study Schematic .......................................................................................10 
 
 


 
 
 
SAP for Protocol INDV-2000-104 
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-2000-104 and is based on 
Amendment 1 of the protocol dated 10 Apr 2023. 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). 
VERSION HISTORY 
Table 1 
SAP Version History Summary 
 
1.1. Objectives and Endpoints 
Each study objective is presented in Table 2 with associated estimands. Intercurrent events 
occur after treatment starts and either preclude the observation of an endpoint or affects its 
interpretation. For the intercurrent event of study discontinuation, the principal stratum 
strategy will be used for pharmacokinetic (PK) endpoints in that only subjects with an 
adequate amount of PK data will be included in the PK Analysis Set (Table 3); for all other 
endpoints, the while-on-treatment strategy will be used since data will be collected only up to 
end of study (EOS) or study discontinuation. Other potential intercurrent events in this study 
are prohibited medications and lifestyle restrictions detailed in protocol sections 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 endpoints (subject would be excluded from the PK 
Analysis Set), to be decided by the sponsor on a case-by-case basis. 
 
SAP 
Version 
SAP 
Finalization 
Date 
Associated 
Protocol  
Version 
Protocol 
Approval  
Date 
Change 
Rationale 
1.0 
 
22May2023 
Amendment 1 
 
10Apr2023 
Not Applicable 
 
Original version 
 


 
 
 
SAP for Protocol INDV-2000-104 
INDV-2000 
Table 2   
Study Objectives and Estimands 
  
Estimand 
Objective 
Clinical Category 
Statistical 
Category 
 
Variable/Endpoint 
Pop- 
ulation 
 
Population-Level Summary 
Primary Objective 
To determine changes in primary PK parameters (maximal and overall plasma exposure) of midazolam and 1-hydroxymidazolam following 
repeated oral doses of INDV-2000. 
PK 
Primary 
Midazolam maximum plasma concentration (Cmax) following 
dosing of midazolam on Day 1 and dosing of midazolam + 
INDV-2000 on Day 15. 
PK 
Geometric mean ratios (Day 
15/Day 1) with 90% 
confidence intervals (CIs) 
 
 
Midazolam area under the plasma concentration-time curve 
from 0 to infinity (AUC0-∞) following dosing of midazolam on 
Day 1 and dosing of midazolam + INDV-2000 on Day 15. 
PK 
Geometric mean ratios (Day 
15/Day 1) with 90% CIs 
 
 
Midazolam area under the plasma concentration-time curve 
from dosing to the last measured concentration (AUClast) 
following dosing of midazolam on Day 1 and dosing of 
midazolam + INDV-2000 on Day 15. 
PK 
Geometric mean ratios (Day 
15/Day 1) with 90% CIs 
  
  
1-hydroxymidazolam Cmax following dosing of midazolam on 
Day 1 and dosing of midazolam + INDV-2000 on Day 15. 
PK 
Geometric mean ratios (Day 
15/Day 1) with 90% CIs 
 
 
1-hydroxymidazolam AUC0-∞ following dosing of midazolam 
on Day 1 and dosing of midazolam + INDV-2000 on Day 15. 
PK 
Geometric mean ratios (Day 
15/Day 1) with 90% CIs 
  
  
1-hydroxymidazolam AUClast following dosing of midazolam 
on Day 1 and dosing of midazolam + INDV-2000 on Day 15. 
PK 
Geometric mean ratios (Day 
15/Day 1) with 90% CIs 
Secondary Objective 
To assess the safety and tolerability of repeated oral doses of INDV-2000 in combination with midazolam as determined by adverse event (AE) 
reporting. 
AEs 
Secondary 
Incidence, seriousness, severity, and relatedness of treatment-
emergent AEs (TEAEs). 
Safety 
Categorical descriptive 
 
 


 
 
 
SAP for Protocol INDV-2000-104 
INDV-2000 
Tertiary/Exploratory Objectives 


 
 
 
SAP for Protocol INDV-2000-104 
INDV-2000 
  
Estimand 
Objective 
Clinical Category 
Statistical 
Category 
 
Variable/Endpoint 
 
Population 
Population-Level 
Summary 
Safety 
Exploratory 
Observed values and changes from baseline (pre-dose Day 1) 
in sedation visual analogue scale (VAS) score through Day 15. 
Safety 
Numeric descriptive 
 
 
Observed values and changes from baseline (Day -1) through 
Day 22 in laboratory results 
Safety 
Numeric or categorical 
descriptive 
 
 
Observed values and changes from baseline (pre-dose Day 1) 
through Day 22 in electrocardiogram (ECG) results  
Safety 
Numeric or categorical 
descriptive 
 
 
Observed values and changes from baseline (pre-dose Day 1) 
through Day 22 in vital signs  
Safety 
Numeric descriptive 
 
 
Observed values and changes from baseline (Day -1) through 
Day 22 in physical examination  
Safety 
Categorical descriptive 
 
 
Observed values and changes from baseline (Day -1) through 
Day 22 in suicidal ideation and behavior [as measured by the 
Columbia-Suicide Severity Rating Scale (C-SSRS)]  
Safety 
Categorical descriptive 
 




 
 
SAP for Protocol INDV-2000-104 
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2. STATISTICAL HYPOTHESES 
This study was not formally powered to test specific statistical hypotheses. Neither an 
estimate of within-subject variability nor no-effect boundaries for 90% CIs of geometric 
means were pre-specified.   
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 
A maximum of 20 participants will be assigned to receive the study drugs. This sample size 
is based on earlier clinical experience and is expected to provide at least 16 evaluable 
participants, defined as participants with plasma concentration-time profiles sufficient for 
calculation of PK parameters during the study. 
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 
 
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. 
Population 
Description 
Screened 
Participants who signed informed consent. 
Safety Analysis Set 
Participants who received at least one dose of study drug.  
PK Analysis Set 
Participants who received at least one dose of study drug, had 
an adequate number of PK samples collected to derive any PK 
parameter, and who had no protocol deviations that would have 
significantly altered plasma concentrations of study drugs.  


 
 
SAP for Protocol INDV-2000-104 
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5.1.2. Programming Environment 
SAS® version 9.4 or higher (SAS Institute, Cary, North Carolina) will be used for statistical 
analyses and for the production of Study Data Tabulation Model (SDTM) and Analysis Data 
Model (ADaM) data sets as well as TFLs.  
5.1.3. Reporting Conventions 
Data will be summarized by visit for visit-based assessments and by treatment for non-visit-
based assessments, if applicable. TFL tables of contents, mock-ups, and specifications are 
provided in a separate document from the SAP. The following reporting conventions will be 
followed: 
• Treatment group names and order in tables and figures for non-visit-based assessments, 
where applicable, will be Midazolam, INDV-2000 + Midazolam, INDV-2000, All 
Subjects; some of these tables may omit the All Subjects groups. Tables and figures for 
visit-based assessments will only show All Subjects and will include a footnote to 
describe treatments administered for each visit, if applicable.   
• Tables and figures will present summaries/analyses by study visit and time point, as 
appropriate.  
• Table column headers and figure legends will include subgroup sample sizes (“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; treatment, if applicable, if the 
assessment is not visit-based; study visit/time point; assessment or collection date/time; 
parameter; and observed value.  
5.1.4. General Analysis Conventions 
Categorical variables will be summarized using frequencies and percentages.  Percentages 
will be reported to one decimal place.  
Continuous variables will be summarized using descriptive statistics (e.g., n, mean, standard 
deviation (SD), distribution percentiles, range). The number of decimal places for minimums 
and maximums will be the same as the 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 Section 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: INDV-2000 or midazolam 
Screening Period: Informed consent to Day -1 Clinic Check-In. 


 
 
SAP for Protocol INDV-2000-104 
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Day -1 Clinic Check-In: clinic check-in to date/time of dosing on Day 1. 
Study Day 1: day of first dose of study drug. 
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 (unless otherwise specified):  
• 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 the first dose of study drug. 
EOS, Subject-Level: Early termination or completion of last scheduled visit. 
EOS, Study-Level: Last visit for 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 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 and for subjects 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 will be summarized in a separate table by number and percentage 
of subjects for each reason reported; the denominator will be the number of screen failures. 
5.3. Primary Endpoints Analysis 
5.3.1. Definition of Endpoints 
The primary endpoints are: 
• Midazolam Cmax following dosing of midazolam on Day 1 and dosing of midazolam + 
INDV-2000 on Day 15 


 
 
SAP for Protocol INDV-2000-104 
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• Midazolam AUC0-∞ following dosing of midazolam on Day 1 and dosing of midazolam + 
INDV-2000 on Day 15 
• Midazolam AUClast following dosing of midazolam on Day 1 and dosing of midazolam + 
INDV-2000 on Day 15 
• 1-hydroxymidazolam Cmax following dosing of midazolam on Day 1 and dosing of 
midazolam + INDV-2000 on Day 15 
• 1-hydroxymidazolam AUC0-∞ following dosing of midazolam on Day 1 and dosing of 
midazolam + INDV-2000 on Day 15 
• 1-hydroxymidazolam AUClast following dosing of midazolam on Day 1 and dosing of 
midazolam + INDV-2000 on Day 15 
5.3.2. Main Analytical Approach 
Estimand strategy: Principal stratum. 
Analysis set: PK (see Table 3).   
Analysis methodology:  Standard non-compartmental methods based on actual sampling 
times will be used to derive parameters for each subject on each of days 1 and 15 (see 
Appendix 6.4.1). A random effects model will be used to estimate the ratio of geometric 
means between absence and presence of INDV-2000, with a 90% CI. In this model, the log-
transformed parameter value will be the dependent variable, day (1 or 15) will be the 
independent variable, and subject will be treated as a random effect.   
For interpretation of AUC geometric mean point estimates, the guidance document Clinical 
Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug 
Interactions Guidance for Industry1 provides the following classification information for an 
investigational drug: 
 
 
 
 
 
In other words, in terms of clinical significance, an investigational drug may be classified as 
a strong, moderate, or weak inducer of a sensitive CYP substrate based on an estimate of the 
AUC geometric mean ratio as follows: 
 
 


 
 
SAP for Protocol INDV-2000-104 
INDV-2000 
 
Classification 
If the point estimate of the 
AUC geometric mean ratio 
Strong inducer 
≤ 0.2 
Moderate inducer 
> 0.2  and ≤ 0.5 
Weak inducer 
> 0.5  and ≤ 0.8 
 
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, relationship and severity of TEAEs, treatment-
emergent serious adverse events (TESAEs), and TEAEs leading to study discontinuation or 
death.  
5.4.2. Main Analytical Approach 
Estimand strategy: While on treatment. 
Analysis set: Safety (see Table 3).   
Analysis methodology:  Descriptive only.  
Intercurrent events and missing data:  AE data will no longer be collected on subjects who 
discontinue early from the study. See Section 6.6.2 (Appendix 6) for handling of missing AE 
information.  
See Section 5.5.2 for details on AE summaries and listings.  
5.5. Exploratory Endpoints Analysis 


 
 
SAP for Protocol INDV-2000-104 
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5.6. Other Safety Analyses 
5.6.1. Study Drug Exposure 
Study drug exposure will be summarized for the Safety Analysis Set as total dose and dose 
duration (days), separately for midazolam and INDV-2000. Dose duration will be defined as 
number of days at least 1 dose was taken. 
5.6.2. Adverse Events 
A TEAE starts at or after the first dose of study drug. AEs will be coded to a System Organ 
Class (SOC) and Preferred Term (PT) using Medical Dictionary for Regulatory Activities 
(MedDRA). Additional details of the coding process, including the current version of the 
dictionary, are described in the Data Management Plan.  
All AEs will be listed for individual subjects. Listings will include SOC, PT, and reported 
term; onset date and time, end date, and duration; treatment-emergence, severity, toxicity 
grade, seriousness and seriousness criteria; relationship to and action taken with 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 drug discontinuation or interruption, and fatal TEAEs will be listed 
separately. 
The incidence and number of all TEAEs, TESAEs, study drug-related TEAEs and TESAEs, 
severe TEAEs, TEAEs with grade 3 or higher toxicity grade, TEAEs leading to study drug  
discontinuation or interruption, and fatal TEAEs will be presented in an overall summary 
table.  
TEAEs, TESAEs, study drug-related TEAEs and 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 


 
 
SAP for Protocol INDV-2000-104 
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and/or PT, the maximum reported level of severity/toxicity will be used at each level of 
summation in the severity/toxicity summary tables. 
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 first dose of study drug. 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 
5.6.3.1. Laboratory Data 
Planned laboratory evaluations (Table 4) will be summarized by analysis visit as observed 
values and, for numeric values, changes from baseline. Normal/abnormal shifts from baseline 
will also be summarized. Abnormal laboratory evaluations will be listed separately. 
Laboratory evaluations done only at screening will be listed but not summarized. Reported 
values of clinical laboratory parameters that include qualifiers (ie, <, ≤, >, ≥) will be listed as 
reported but will be summarized without the qualifier. 
 
 


 
 
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Table 4 
Planned Laboratory Evaluations 
Haematology 
 
Serum Chemistry * 
• 
Haemoglobin 
• 
Haematocrit  
• 
Total and differential leukocyte count 
• 
Red blood cell count 
• 
Platelet count 
 
Coagulation 
• 
Prothrombin time/INR 
• 
Activated partial thromboplastin 
 
 
• 
Blood Urea Nitrogen 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase (ALP) 
• 
AST 
• 
ALT 
• 
Gamma-glutamyl Transferase 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Glucose (fasting) 
• 
Creatinine ** 
• 
Total protein  
• 
Total cholesterol  
• 
Triglycerides  
• 
Creatine phosphokinase 
 
Urinalysis 
 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Protein *** 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood *** 
• 
Nitrite*** 
• 
Urobilinogen 
• 
Leukocyte esterase *** 
 
• 
HIV-1; HIV-2 (screening only) 
• 
HBsAg (screening only) 
• 
HCV antibodies (screening only) 
• 
Urine drug screen 
 
Opiates § 
 
Opioids 
 
Amphetamines 
 
Barbiturates 
 
Benzodiazepines 
 
Cocaine 
 
Cannabinoids 
 
Fentanyl  
 
Oxycodone  
• 
Urine alcohol screen 
• 
Serum pregnancy test (for females only; screening 
only) 
• 
Urine pregnancy test (for females only) 
• 
FSH (for PMP females only; screening only) 
• 
COVID-19 PCR (check-in only) 
 
* 
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. 
** At the Screening Visit, creatinine clearance will be calculated using the Cockcroft-Gault formula. 
*** If urinalysis is abnormal for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
 


 
 
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5.6.3.2. Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry) will be summarized as observed values and changes from baseline by 
analysis visit and time point. 
5.6.3.3. Electrocardiogram (ECG) Data 
Numeric 12-lead ECG parameters [heart rate, PR interval, QRS duration, QT interval, 
Fridericia’s corrected QT interval (QTcF)] will be summarized as observed values and 
changes from baseline by analysis visit and time point. ECG interpretation (normal, abnormal 
not clinically significant, abnormal clinically significant) will be summarized by visit and 
time point as shifts from baseline. 
5.6.3.4. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The composite endpoints Suicidal Ideation and Suicidal Behavior will be derived from the 
following 10 binary C-SSRS questions, reordered from the actual scale to facilitate the 
derivation: 
 
Question 1  
Wish to be Dead 
Question 2  
Non-specific Active Suicidal Thoughts 
Question 3  
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Question 4 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Question 5 
Active Suicidal Ideation with Specific Plan and Intent 
Question 6 
Preparatory Acts or Behaviour 
Question 7  
Aborted Attempt 
Question 8 
Interrupted Attempt 
Question 9 
Actual Attempt (non-fatal) 
Question 10 
Completed Suicide 
Suicidal Ideation is derived as “yes” if any of Question 1-5 has a “yes” response. Suicidal 
Behavior is derived as “yes” if any of Question 6-10 has a “yes” response. If there are zero 
“yes” responses and at least one question has a missing response, the derived composite will 
be missing. Suicidal Ideation and Suicidal Behavior will be summarized as categorical 
variables by analysis visit. 


 
 
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5.7. Other Analyses 
5.7.1. Demographic and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized separately for the safety 
and PK analysis sets, if different. Parameters to be summarized will include age, sex, race, 
ethnicity, fertility status, 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 first administration of study drug or were taken 
by subjects who never took study drug. 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. 
 
 


 
 
SAP for Protocol INDV-2000-104 
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6. SUPPORTING DOCUMENTATION 
 


 
 
SAP for Protocol INDV-2000-104 
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6.1. Appendix 1: List of Abbreviations 
Abbreviation 
Term 
ADaM 
Analysis Data Model 
AE 
adverse event 
ATC 
Anatomic Therapeutic Chemical 
AUC 
area under the curve 
AUC0-12h 
area under the curve from 0 to 12 hours post dose 
AUC0-∞ 
area under the curve from 0 to infinity 
AUClast 
area under the curve from dosing to the last measured concentration 
BLQ 
below limit of quantification 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
Ctrough 
Trough concentration 
CV 
coefficient of variation 
CYP 
cytochrome P450 
CYP3A4 
cytochrome P450 3A4  
ECG 
electrocardiogram 
EOS 
end of study 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic 
PT 
Preferred Term 
QTcF 
Fridericia’s corrected QT interval 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
t1/2 
apparent terminal half-life 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TFLs 
tables, figures, and listings 
Tmax 
time of maximum plasma concentration 
VAS 
visual analogue scale 
WHO-DD 
World Health Organization Drug Dictionary 
 
6.2. Appendix 2: Changes to Protocol-Planned Analyses 
None. 
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.   


 
 
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6.4. Appendix 4: Endpoint Derivations 
6.4.1. Pharmacokinetic Endpoints 
6.5. Appendix 5: Statistical Methodology Details 
Statistical programming will be done using SAS version 9.4 (or later) on a Windows 10 
Enterprise (or later) operating system. Plasma PK parameters will be calculated using 
Phoenix™ WinNonlin® (Version 8.3.4 or higher, Certara, LP). 
6.5.1.1. Concentration 


 
 
SAP for Protocol INDV-2000-104 
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6.5.1.2. Plasma PK Parameters 
6.6. Appendix 6: Methods to Manage Missing Data 
6.6.1. BLQ PK Concentrations 
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. 
 


 
 
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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. 
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 first study drug administration. 
 
• Missing start month, day, time if start year is equal to or after year of first study drug 
administration, unless it can be deduced from non-missing components of AE end date 
that AE ended before first study drug administration. 
 
• Missing start day and time if start year is after year of first study drug administration or if 
start year is equal to year of first study drug administration and month is equal to or after 
month of first study drug administration, unless AE end date is before date of first study 
drug administration. 
 
• Missing start time if start date is on or after first date of study drug administration. 
 
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 first study drug, medication/therapy is prior. 
• If end date is equal to or after date of first study drug, medication/therapy is 
concomitant. 


 
 
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Non-missing end year and month, missing end day 
• If end year is before year of first study drug, medication/therapy is prior. 
• If end year is equal to year of first study drug and end month is before month of first 
study drug, medication/therapy is prior. 
• If end year is equal to year of first study drug and end month is equal to or after month 
of first drug, medication/therapy is concomitant. 
• If end year is after year of first study drug, medication/therapy is concomitant. 
Non-missing end year, missing end month and day 
• If end year is before year of first study drug, medication/therapy is prior. 
• If end year is equal to or after year of first study drug, medication/therapy is 
concomitant. 
Missing end year, month, and day 
• Medication/therapy is concomitant if subject was dosed; otherwise, 
medication/therapy is prior. 
6.7. Appendix 7: Data Set Descriptions 
Trial data sets will consist of CRF exports and external data files. External files may be used 
for protocol deviations and data from the central laboratory, for example. 
 
 


 
 
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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 Drug Interaction Studies — Cytochrome 
P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry, January 
2020.