Conditions: Healthy Volunteer
Keywords: Pharmacokinetics S-648414 Food effect Antiretroviral Drug-drug interaction
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 98
Healthy volunteers: yes

Brief summary:
The primary objective of Part 1 of the study is to evaluate the safety and tolerability of S-648414 after administration of a single oral dose of S-648414 in healthy adult study participants.

The primary objective of Part 2 is to evaluate the safety and tolerability of S-648414 after administration of multiple oral doses of S-648414 in healthy adult study participants.

The primary objectives of Part 3 are evaluate the safety and tolerability of S-648414 after administration of multiple oral doses of S-648414 in healthy adult study participants, and to evaluate the effect of S-648414 on the pharmacokinetics (PK) of dolutegravir and the effect of dolutegravir on the PK of S-648414 in healthy adult study participants.

Detailed description:
Amendment 2 of the study Protocol added a third part (Part 3) to the study. The revised Official Title for the Protocol is:

"A Phase 1, Randomized, Double-Blind, Single-Ascending-Dose, and Food Effect Study to Assess the Safety, Tolerability, Ventricular Repolarization, and Pharmacokinetics of S-648414 in Healthy Adult Study Participants (Part 1); A Phase 1, Randomized, Double-Blind, Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of S-648414 and A Drug-Drug Interaction Study with the CYP3A Substrate, Midazolam, in Healthy Adult Study Participants (Part 2); and A Phase 1 Open-Label Study to Assess the Effect of S-648414 on the Pharmacokinetics of Dolutegravir and the Effect of Dolutegravir on the Pharmacokinetics of S-648414 in Healthy Adult Study Participants (Part 3)"

Arms:
arm 1: Participants received a single oral dose of matching placebo in a fasted state on Day 1. arm 2: Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. arm 3: Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. arm 4: Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1 followed by a single dose of S-648414 in a fed state (after a high-fat meal) on Day 14. arm 5: Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. arm 6: Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. arm 7: Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1. arm 8: Participants received matching placebo once a day on Days 1 to 14 and a single oral dose of 5 mg midazolam alone on Day -2 and co-administered with the placebo dose on Day 14. arm 9: Participants received 50 mg S-648414 once a day on Days 1 to 14 and a single oral dose of 5 mg midazolam alone on Day -2 and co-administered with the S-648414 dose on Day 14. arm 10: Participants received 30 mg S-648414 once a day on Days 1 to 14 and a single oral dose of 5 mg midazolam alone on Day -2 and co-administered with the S-648414 dose on Day 14. arm 11: Participants received 50 mg dolutegravir orally once a day on Days 1 to 7, 100 mg S-648414 orally once a day on Days 15 to 21, and 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. arm 12: Participants received 50 mg dolutegravir orally once a day on Days 1 to 7, 200 mg S-648414 orally once a day on Days 15 to 21, and 50 mg dolutegravir co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.

Interventions: intervention 1: S-648414 intervention 2: Placebo intervention 3: Midazolam intervention 4: Dolutegravir
Intervention descriptions: intervention 1: Tablet for oral administration intervention 2: Tablet for oral administration intervention 3: Solution for oral administration intervention 4: Tablet for oral administration

Protocol document:
Prot_000.pdf: 
 
Shionogi Study Title: 
A Phase 1, Randomized, Double-Blind, Single-
Ascending-Dose, and Food Effect Study to Assess the 
Safety, Tolerability, Ventricular Repolarization, and 
Pharmacokinetics of S-648414 in Healthy Adult Study 
Participants (Part 1); A Phase 1, Randomized, Double-
Blind, Multiple-Ascending-Dose Study to Assess the 
Safety, Tolerability, and Pharmacokinetics of S-648414 
and A Drug-Drug Interaction Study with the CYP3A 
Substrate, Midazolam, in Healthy Adult Study Participants 
(Part 2); and A Phase 1 Open-Label Study to Assess the 
Effect of S-648414 on the Pharmacokinetics of 
Dolutegravir and the Effect of Dolutegravir on the 
Pharmacokinetics of S-648414 in Healthy Adult Study 
Participants (Part 3) 
Shionogi Study Number: 
1908T0911 
ClinicalTrials.gov 
Registration No. 
NCT04147715 
Study Document 
Protocol Amendment 6                           June 17, 2020 
 
History of Protocol Amendments 
 
Original 
July 30, 2019 
• 
Modifies the dose in Groups G and H in Part 2 
Amendment 1 
December 23, 2019 
• 
Adds Part 3 to study the effect of S-648414 on the pharmacokinetics of dolutegravir and the 
effect of dolutegravir on the PK of S-648414  
Amendment 2 
January 27, 2020 
• Adjusts the dose for Group H and Group I 
Amendment 3 
February 9, 2020 
• Adds ophthalmological examinations to Part 3 of the study 
Amendment 4 
March 16, 2020 
• Adds a second center and region to the study 
• Change doses in Part 3 of the study 
Amendment 5 
May 6, 2020 
• Adds text to allow the investigator to choose between outpatient or inpatient status 
during Days 9 to 13 between Periods 1 and 2 of Part 3 
Amendment 6 
June 17, 2020 
 




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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 6 
17 Jun 2020 
Amendment 5 
06 May 2020 
Amendment 4 
16 Mar 2020 
Amendment 3 
09 Feb 2020 
Amendment 2 
27 Jan 2020 
Amendment 1 
23 Dec 2019 
Original Protocol 
30 Jul 2019 
 
Amendment 6 (17 Jun 2020) 
Overall Rationale for the Amendment: 
This amendment allows the investigator to choose between outpatient or inpatient status 
during Days 9 to 13 between Periods 1 and 2 of Part 3.  
A high-level description of the changes and brief scientific rationale are outlined in the 
following: 
Section(s) # and Name(s) 
Description of Change 
Brief Rationale 
1.1 Synopsis, Overall Design, 
Part 3, Figure 1-4, 
4.1 Overall Design, and 
Table 4-3 
Added text to change the 
outpatient period (Days 9 to 
13 between Periods 1 and 2 of 
Part 3) to be either outpatient 
or inpatient. 
This will allow the investigator to 
determine if a study participant should 
remain inpatient or can be outpatient 
during Days 9 to 13. 
1.1 Synopsis, Safety 
Assessments, Figure 1-4, 
Figure 1-5, and 8.2.2 Vital 
Signs 
Removed specification of oral 
body temperature for Part 3. 
Any method of temperature 
measurement is acceptable, axillary 
temperature is standard of care in Japan. 
7.1 Discontinuation of Study 
Intervention 
Allow replacement of study 
participants who prematurely 
discontinue during Part 3. 
Allows study participants to be replaced 
during Part 3. 
 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................2 
1. 
PROTOCOL SUMMARY ...........................................................................................7 
1.1 
Synopsis .............................................................................................................7 
1.2 
Schema .............................................................................................................22 
1.3 
Schedule of Activities ......................................................................................23 
2. 
INTRODUCTION .....................................................................................................37 
2.1 
Study Rationale ................................................................................................37 
2.2 
Background ......................................................................................................37 
2.3 
Benefit/Risk Assessment .................................................................................38 
3. 
OBJECTIVES AND ENDPOINTS ...........................................................................39 
4. 
STUDY DESIGN ......................................................................................................40 
4.1 
Overall Design .................................................................................................40 
4.2 
Scientific Rationale for Study Design..............................................................44 
4.3 
Justification for Dose .......................................................................................44 
4.4 
End of Study Definition ...................................................................................45 
5. 
STUDY POPULATION ............................................................................................45 
5.1 
Inclusion Criteria .............................................................................................45 
5.2 
Exclusion Criteria ............................................................................................46 
5.3 
Lifestyle Considerations ..................................................................................48 
5.3.1 
Meals and Dietary Restrictions ..............................................................48 
5.3.2 
Activity ..................................................................................................49 
5.4 
Screen Failures .................................................................................................49 
6. 
STUDY INTERVENTION ........................................................................................50 
6.1 
Study Intervention(s) Administered .................................................................50 
6.2 
Preparation/Handling/Storage/Accountability of Study Intervention ..............51 
6.3 
Measures to Minimize Bias: Randomization and Blinding .............................52 
6.4 
Study Intervention Compliance .......................................................................52 
6.5 
Prior Therapy/Concomitant Therapy ...............................................................52 
6.6 
Dose Modification of Study Intervention ........................................................53 
6.6.1 
Part 1 – Single Dosing ...........................................................................56 
6.6.2 
Part 2 – Multiple Dosing ........................................................................56 
6.6.3 
Part 3 – Coadministration with Dolutegravir .........................................57 
6.7 
Intervention After the End of the Study ...........................................................57 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................58 
7.1 
Discontinuation of Study Intervention .............................................................58 
7.1.1 
Discontinuation of Study Intervention for Abnormal Liver Function ...58 


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7.1.2 
Discontinuation of Study Intervention for Cardiac Changes .................58 
7.1.3 
Discontinuation of Study Intervention for Pregnancy ...........................58 
7.2 
Study Participant Discontinuation/Withdrawal from the Study ......................59 
7.3 
Lost to Follow-up .............................................................................................59 
8. 
STUDY ASSESSMENTS AND PROCEDURES .....................................................60 
8.1 
Efficacy Assessments.......................................................................................60 
8.2 
Safety Assessments ..........................................................................................60 
8.2.1 
Physical Examinations ...........................................................................61 
8.2.2 
Vital Signs ..............................................................................................61 
8.2.3 
Electrocardiograms ................................................................................61 
8.2.4 
Clinical Safety Laboratory Assessments ...............................................64 
8.2.5 
Ophthalmological Examinations ............................................................64 
8.3 
Adverse Events and Serious Adverse Events ..................................................65 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information .......................................................65 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ......65 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events ..................66 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .........66 
8.3.5 
Pregnancy ...............................................................................................66 
8.3.6 
Adverse Events of Special Interest ........................................................67 
8.4 
Special Situations – Abuse, Misuse, Overdose, and Medication Error ...........67 
8.4.1 
Treatment of Overdose ..........................................................................67 
8.5 
Pharmacokinetics .............................................................................................68 
8.6 
Pharmacodynamics ..........................................................................................68 
8.7 
Genetics............................................................................................................69 
8.8 
Biomarkers .......................................................................................................69 
8.9 
Medical Resource Utilization and Health Economics .....................................69 
9. 
STATISTICAL CONSIDERATIONS ......................................................................70 
9.1 
Statistical Hypotheses ......................................................................................70 
9.2 
Sample Size Determination..............................................................................70 
9.3 
Populations for Analyses .................................................................................70 
9.4 
Statistical Analyses ..........................................................................................71 
9.4.1 
Disposition .............................................................................................71 
9.4.2 
Demographics, Treatment Compliance, and Prior and Concomitant 
Therapies ................................................................................................71 
9.4.3 
Safety Analyses ......................................................................................72 
9.4.4 
Other Analyses .......................................................................................72 
9.5 
Interim Analyses ..............................................................................................80 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL  
CONSIDERATIONS .................................................................................................81 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..........81 
10.1.1 
Regulatory and Ethical Considerations ..................................................81 
10.1.2 
Financial Disclosure...............................................................................81 
10.1.3 
Informed Consent Process .....................................................................82 
10.1.4 
Data Protection.......................................................................................82 
10.1.5 
Dissemination of Clinical Study Data....................................................83 
10.1.6 
Data Quality Assurance .........................................................................83 
10.1.7 
Source Documents .................................................................................83 
10.1.8 
Study and Site Closure ...........................................................................84 
10.2 
Appendix 2: Clinical Laboratory Tests ............................................................84 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .............................................................86 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ......................................................................................................90 
10.5 
Appendix 5: Genetics .......................................................................................93 
10.6 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ...94 
10.7 
Appendix 7: Abbreviations and Acronyms......................................................96 
10.8 
Appendix 8: Protocol Amendment History .....................................................99 
11. REFERENCES ........................................................................................................112 
 
LIST OF IN-TEXT TABLES 
Table 1-1 
Objectives and Endpoints ....................................................................... 8 
Table 1-2 
Part 1 Dose Groups ............................................................................... 10 
Table 1-3 
Part 2 Dose Groups ............................................................................... 11 
Table 1-4 
Part 3 Treatment Schedule .................................................................... 12 
Table 3-1 
Objectives and Endpoints ..................................................................... 39 
Table 4-1 
Part 1 Dose Groups ............................................................................... 41 
Table 4-2 
Part 2 Dose Groups ............................................................................... 42 
Table 4-3 
Part 3 Treatment Schedule .................................................................... 43 
Table 6-1 
Study Intervention(s) ............................................................................ 50 
Table 6-2 
Number of Tablets (S-648414 or Placebo) per Dose Group................. 51 
Table 6-3 
Sequence of Steps ................................................................................. 54 
Table 8-1 
T-wave Morphology and U-wave Presence Categories (Assessed 
Manually) ............................................................................................. 63 
Table 10-1 
Protocol-required Safety Laboratory Assessments ............................... 85 
Table 10-2 
Highly Effective Contraceptive Methods ............................................. 91 


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LIST OF IN-TEXT FIGURES 
Figure 1-1 
Study Schematic – Part 3 ...................................................................... 22 
Figure 1-2 
Schedule of Activities – Part 1.............................................................. 23 
Figure 1-3 
Schedule of Activities – Part 2, Groups G and H ................................. 27 
Figure 1-4 
Schedule of Activities – Part 3, Period 1, Groups I and J ..................... 31 
Figure 1-5 
Schedule of Activities – Part 3, Periods 2 and 3, Groups I and J ......... 34 
 


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1. PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title:  
A Phase 1, Randomized, Double-Blind, Single-Ascending-Dose, and Food Effect Study 
to Assess the Safety, Tolerability, Ventricular Repolarization, and Pharmacokinetics of 
S-648414 in Healthy Adult Study Participants (Part 1); A Phase 1, Randomized, Double-
Blind, Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of S-648414 and A Drug-Drug Interaction Study with the CYP3A 
Substrate, Midazolam, in Healthy Adult Study Participants (Part 2); and A Phase 1 
Open-Label Study to Assess the Effect of S-648414 on the Pharmacokinetics of 
Dolutegravir and the Effect of Dolutegravir on the Pharmacokinetics of S-648414 in 
Healthy Adult Study Participants (Part 3) 
Protocol Number: 1908T0911 
Compound Number: S-648414 
Short Title: Phase 1 Study of S-648414 
Rationale:  
S-648414 is a novel antiretroviral agent that is being developed as a treatment for human 
immunodeficiency virus (HIV-1) infection in combination with other antiretroviral agents 
to fully suppress HIV-1 viremia. Based on a full pre-clinical development program of 
S-648414, this study is expected to be conducted safely and the minimum and maximum 
doses tested have been determined based on in-vitro efficacy estimations and animal 
Good Laboratory Practice (GLP)-compliant toxicology studies. These Phase 1 
assessments will describe the safety, tolerability, and pharmacokinetics (PK) of S-648414 
following first-in-human dosing, both single- and multiple-ascending dosing 
(SAD/MAD), food effect, effect on electrocardiogram (ECG) parameters, and effect on 
the PK of midazolam, a cytochrome P450 3A (CYP3A) probe, as well as the effect of 
S-648414 on the PK of dolutegravir and the effect of dolutegravir on the PK of S-648414. 
The study will permit evaluation of dosing and safety in the clinical setting to inform and 
facilitate studies in individuals living with HIV-1 infection. 
 
 




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Overall Design: 
The study is a multicenter, randomized, double-blind (Parts 1 and 2) and open-label 
(Part 3), placebo-controlled, sequential group study in healthy adult study participants. 
The study consists of Part 1 (SAD, food effect, and effects on ECG parameters including 
concentration-QTc analysis), Part 2 (MAD and drug-drug interaction with the CYP3A 
substrate), and Part 3 (the effect of S-648414 on the PK of dolutegravir and the effect of 
dolutegravir on the PK of S-648414). The sequence of steps in Parts 1, 2, and 3 are 
summarized in Table 1-5. 
Part 1: 
The study consists of a Screening period (Days −28 to −2), admission to the clinical 
research unit (CRU, Day −1), single administrations of S-648414 or matching placebo 
(Day 1), discharge from the CRU (Day 5), and a Follow-up visit (Day 10 ± 2) (see 
Figure 1-2). 
In Groups A, B, D, E, and F, eligible healthy adult study participants will be assigned to 
1 of 5 ascending dose groups (10 to 1000 mg) and receive a single oral dose of S-648414 
or placebo in a fasted state with 6 study participants per dose group receiving active drug 
and 2 study participants per dose group receiving placebo. Administration initiates from 
the lowest dose group, and the next group does not initiate until the Follow-up period has 
been completed for the previous group except for A-2 (see Table 1-2).  
In Group C, 8 study participants will be assigned to S-648414, and 2 study participants 
will be assigned to placebo. Study participants assigned to the 100-mg group will receive 
a single oral dose of S-648414 in a fasted state (Group C-1), followed by a single dose of 
S-648414 in a fed state (high-fat meal) (Group C-2). Each episode of dosing will be 
separated by a washout period of at least 14 days. 


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Table 1-2 
Part 1 Dose Groups 
Group Label 
S-648414 Dose 
Number of Active 
Study Participants 
Number of Placebo 
Study Participants 
Group A  
(Group A-1 and A-2)a 
10 mg 
6 
2 
Group B 
30 mg 
6 
2 
Group C  
(Group C-1 and C-2) 
100 mg 
8 
2 
Group D 
250 mg 
6 
2 
Group E 
500 mg 
6 
2 
Group F 
1000 mg 
6 
2 
a 
Because this is a first-in-human administration, the initial dose group (Group A) is divided into 
Group A-1 including 2 study participants (1 S-648414 and 1 placebo) and Group A-2 including 
6 study participants (5 S-648414 and 1 placebo). Study participants in Group A-2 will receive 
study intervention (S-648414 or placebo) in a sentinel dosing sequence, ie, only after confirmation 
that there are no clinical concerns in Group A-1 within 24 hours postdose.  
The doses may be changed depending on the results of the safety, tolerability, and PK in 
the preceding group(s), if necessary. The highest dose will not exceed 1000 mg. 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group. 
The next dose group will not be conducted if any of the following criteria are met: 
● Any study participant experiences a treatment-related serious adverse event 
(SAE) (ie, treatment-emergent SAE considered related to the study intervention 
[S-648414 or placebo] by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related adverse 
event (AEs) 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
See Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of intensity 
(including HIV grading system), assessment of causality, and procedures for recording, 
evaluating, follow-up, and reporting. 
Part 2: 
Eligible healthy adult study participants are assigned to 1 of 2 dose groups (50 mg in 
Group G or 30 mg in Group H) and receive multiple oral doses of S-648414 tablet or 
placebo in a fed state with 8 study participants receiving active drug and 2 study 
participants receiving placebo per group (see Table 1-3). Administration of the next dose 
group (Group H) will not initiate until the Follow-up period has been completed for the 
previous group (Group G).  
In Groups G and H, the study consists of a Screening period (Days −28 to −4), 
admission to the CRU (Day −3), administration of midazolam 5 mg (Day −2 and Day 14) 


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and multiple administrations of S-648414 or matching placebo (Days 1 to 14), discharge 
from the CRU (Day 19), and a Follow-up visit (Day 25 ± 2) (see Figure 1-3). 
All study participants will receive a single oral dose of midazolam 5 mg alone on Day -2 
and coadministered with the S-648414/placebo dose on Day 14. Study participants will 
receive S-648414/placebo once daily (QD) on Days 1 to 14 (Group G will receive 50 mg 
and Group H will receive 30 mg).  
Table 1-3 
Part 2 Dose Groups 
Group Label 
S-648414 Dose 
Number of Active 
Study Participants 
Number of Placebo 
Study Participants 
Length of 
Treatment (Days) 
Group G 
50 mg 
8 
2 
14 
Group H 
30 mg 
8 
2 
14 
 
The doses, mode of administration, frequency (ie, QD or twice daily [BID]), dietary 
condition (ie, fasted or fed), or length of administration may be changed depending on the 
results of the safety, tolerability, and PK in the preceding group(s), if necessary. 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group.  
The next dose group will not be conducted if any of the following criteria are met: 
● Any study participant experiences a treatment-related SAE (ie, treatment-
emergent SAE considered related to the study intervention [S-648414 or placebo] 
by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
See Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of intensity 
(including HIV grading system), assessment of causality, and procedures for recording, 
evaluating, follow-up, and reporting. 
Part 3: 
Part 3 is an open-label, non-randomized, 1-sequence, 3-period study.  
A total of 14 healthy adult study participants will be enrolled in Group I of Part 3; an 
additional 14 healthy adult study participants will be enrolled in Group J of Part 3. 
Part 3 will consist of:  
 Screening period (Days −28 to −2) 
 Period 1 (admission to CRU on Day -1 with continued confinement until Day 8) 
 Mandatory 7-day washout between the last dose of study intervention in Period 1 
and the first dose of study intervention in Period 2 


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o Day 8 of Period 1 (no dose) 
o Days 9 to 13 (5-days, no dose) 
The 5-day period can be inpatient or outpatient and will be decided at the 
discretion of the investigator. 
o Day 14 of Period 2 (no dose) 
 Period 2 (confinement: Days 14 to 21)  
 Period 3 (confinement: Days 22 to 29) 
 Follow-up visit (7 days after discharge from the CRU of Period 3 
[Day 36] ± 2 days) 
Study participants will receive:  
 Dolutegravir (50 mg orally QD for 7 days) in the fed state during Period 1  
 S-648414 alone (100 mg orally QD for 7 days in Group I and 200 mg orally QD 
for 7 days in Group J) in the fed state during Period 2 
 S-648414 (100 mg orally QD for 7 days in Group I and 200 mg orally QD for 
7 days in Group J) coadministered with dolutegravir (50 mg orally QD for 7 days) 
in the fed state during Period 3 
See Table 1-4 for the treatment schedule and Figure 1-1 for the study schematic. 
Table 1-4 
Part 3 Treatment Schedule 
Group Label 
Number of 
Study 
Participants 
Period 1a 
Period 2a 
Period 3 
Group I 
14 
Dolutegravir 50 mg 
QD for 7 days 
S-648414 100 mg 
QD for 7 days 
S-648414 100 mg + 
dolutegravir 50 mg 
QD for 7 days 
Group J 
14 
Dolutegravir 50 mg 
QD for 7 days 
S-648414 200 mg 
QD for 7 days 
S-648414 200 mg + 
dolutegravir 50 mg 
QD for 7 days 
QD = once daily 
a 
There will be a 7-day washout period between Periods 1 and 2; the 7-day washout period includes the 
time when the study participant will not receive study intervention on the last day of Period 1 and the 
first day of Period 2. 
The doses, mode of administration, frequency (ie, QD or BID), dietary condition (ie, 
fasted or fed), or length of administration may be changed, if necessary, by the sponsor 
depending on the results of the safety, tolerability, and PK in the preceding group(s). 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group.  
The next dose group will not be conducted if any of the following criteria are met: 


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● Any study participant experiences a treatment-related SAE (ie, treatment-
emergent SAE considered related to S-648414 by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
See Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of intensity 
(including HIV grading system), assessment of causality, and procedures for recording, 
evaluating, follow-up, and reporting. 
Inclusion Criteria: 
Study participants are eligible to be included in the study only if all of the following 
criteria apply:  
1. Male or female adults ≥ 18 years in USA or ≥ 20 years in Japan to ≤ 55 years of 
age, at the time of signing the informed consent form (ICF). 
a) Specific to Japan sites: enrollment in Part 3 (Group I and J) will consist of 
only White or Black or African American race. 
2. Capable of giving signed informed consent as described in Section 10.1 
(Appendix 1), which includes compliance with the requirements and restrictions 
listed in the ICF and in this protocol. 
3. Body mass index (BMI) ≥ 18.5 to < 32.0 kg/m2 at the Screening visit． 
4. Considered medically healthy as determined by the investigator or subinvestigator 
(suitably qualified), based on medical history and clinical evaluations including 
physical examination, clinical laboratory tests, vital sign measurements, and 
12-lead ECG at Screening and at upon admission to the CRU and prior to 
administration of study intervention on Day 1. Clinical evaluations during 
Screening can be repeated (for confirmatory purposes or if additional information 
is required to assess study participant’s eligibility) at the discretion of the 
investigator; repeated procedures must be performed within the same Screening 
window. 
5. Female study participants must not be a woman of childbearing potential (see 
Section 10.4 [Appendix 4]) and must either be postmenopausal (defined as no 
menses for 12 months without an alternative medical cause; follicle-stimulating 
hormone [FSH] to be tested for confirmation at Screening) or premenopausal with 
1 of the following documented: hysterectomy, tubal ligation, bilateral 
salpingectomy, or bilateral oophorectomy. 
6. Male study participants must agree to use contraception as detailed in 
Section 10.4 (Appendix 4) during the treatment period and for at least 3 months 
after the last dose of study intervention. 
Exclusion Criteria: 
Study participants are excluded from the study if any of the following criteria apply:  


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Medical Conditions 
1. Considered by the investigator or subinvestigator (suitably qualified) to be 
ineligible for the study due to a history of or current condition of significant 
metabolic or endocrine, hepatic, renal, hematological, pulmonary, cardiovascular, 
gastrointestinal (GI), urological, immunological, neurological, or psychiatric 
disorders with clinical manifestations.  
2. History or presence of cancer in last 5 years except for nonmelanoma skin 
cancers.  
3. Risk factors for:  
a. Torsades de Pointes (eg, heart failure, cardiomyopathy, or family history of 
Long QT Syndrome or Brugada Syndrome)  
b. Unexplained syncope, sick sinus syndrome, second- or third-degree 
atrioventricular (AV) block, myocardial infarction, pulmonary congestion, 
cardiac arrhythmia, angina, prolonged QT interval, or conduction 
abnormalities  
4. History of GI surgery or disease including, but not limited to, gastric band/gastric 
resection and/or intestinal resection and or duodenal disease (ie, celiac disease) 
that may result in clinically significant malabsorption (except for an 
appendectomy). 
5. History of hypersensitivity or severe side effects induced by a drug.  
6. Any condition requiring medication and/or other treatment, such as dietary 
restriction and physical therapy.  
7. History of significant multiple and/or severe allergic symptoms including food 
allergy (NOTE: Study participants with seasonal allergies may participate unless 
they have ongoing symptoms).  
Prior/Concomitant Therapy 
8. Used drugs or substances known to be inducers or inhibitors of cytochrome P450 
enzymes and/or P-glycoprotein within 28 days prior to admission to the CRU. 
9. Used prescription or over-the-counter (OTC) drugs, antacids, proton pump 
inhibitors, H2 antagonists, Chinese herbal medicines, oral cannabidiol, vitamins, 
minerals, herbal, and dietary supplements within 14 days prior to admission to the 
CRU. 
Caffeine, Alcohol, Recreational Drugs, and Tobacco or Nicotine 
10. Refuses to abstain from ingesting caffeine- or xanthine-containing 
products/medications (eg, coffee, tea, cola drinks, other caffeinated beverages, or 
chocolate) from 24 hours prior to admission to the CRU or refuses to refrain from 
consuming such products throughout the study (including Follow-up period). 
11. Consumed alcohol or used alcohol-containing products within 72 hours prior to 
admission to the CRU or refuses to refrain from consuming such products 
throughout the study (including Follow-up period).  


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12. History of recreational drug use in the previous 6 months or has a history of 
problematic alcohol use (defined as study participants who regularly consume 
excessive amounts of alcohol, defined as > 3 glasses of alcoholic beverages per 
day (1 glass is approximately equivalent to: beer [284 mL/10 ounces (oz.)], wine 
[125 mL/4 oz.] or distilled spirits [25 mL/1 oz.]).  
13. A positive drug or alcohol screen at the Screening visit or upon admission to the 
CRU. 
14. Used tobacco- or nicotine-containing products (including cigarette, pipe, cigar, 
chewing, nicotine patch, or nicotine gum) within 6 months prior to admission to 
the CRU or refuses to refrain from using tobacco- or nicotine-containing products 
throughout the study (including Follow-up period). 
Meals and Dietary Restrictions 
15. Consumed grapefruit, grapefruit juice, Seville orange juice, orange juice, apple 
juice, vegetables from the mustard green family (eg, kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels sprouts, mustard greens), or charbroiled meats 
within 7 days prior to admission to the CRU or refuses to refrain from consuming 
such products throughout the study (including Follow-up period).  
Diagnostic Assessments 
16. A corrected QT (QTc) interval of > 450 msec for males and > 470 msec for 
females (Fridericia’s method) at the Screening visit or upon admission to the 
CRU. 
17. Systolic blood pressure is outside the range of 90 to 140 mm Hg, diastolic blood 
pressure is outside the range of 50 to 90 mm Hg, or pulse rate is outside the range 
of 40 to 100 beats per minute (bpm) or considered ineligible by the investigator or 
subinvestigator at the Screening visit or upon admission to the CRU. 
18. Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase 
(AST) values are greater than the upper limit of normal (ULN), or estimated 
glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 at Screening or upon 
admission to the CRU. 
19. A positive serological test for untreated syphilis, positive hepatitis B surface 
antigen, positive hepatitis C virus antibody, or positive human immunodeficiency 
virus (HIV) antigen/antibody result at the Screening visit.  
Prior/Concurrent Clinical Study Experience 
20. Participated in any other investigational trials or has been exposed to other 
investigational drugs within 28 days or 5 half-lives of the previously administered 
investigational drug (date derived from last study procedure [blood collection or 
dosing] of previous trial), whichever is longer, prior to admission to the CRU.  
21. Previously received S-648414. 
Other Exclusions 
22. Poor venous access. 


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23. Donated blood (> 500 mL) or had significant blood loss within 56 days of study 
admission to the CRU or donated plasma within 7 days prior to until admission to 
the CRU.  
24. Considered inappropriate for participation in the study for any reason by the 
investigator or subinvestigator. 
Number of Study Participants: 
Up to 50 healthy adult study participants in Part 1, 20 healthy adult study participants in 
Part 2, and 28 healthy adult study participants in Part 3. 
Study Intervention Groups and Duration: 
Test Drug, Dose, and Mode of Administration: 
Part 1: 
S-648414 tablets 10 mg, 100 mg, or a combination of both in the fasted (Groups A, B, 
C-1, D, E, and F) or fed state (Group C-2) 
Part 2:  
S-648414 tablets 10 mg in the fed state (Groups G and H) 
Part 3:  
S-648414 tablets 100 mg in the fed state (Groups I and J) 
Control Drug, Dose, and Mode of Administration: 
Matching placebo tablet, oral administration in the fasted or fed state 
Other Treatment, Dose, and Mode of Administration: 
Part 2:  
Midazolam 5 mg (midazolam 2 mg/mL syrup 2.5 mL), oral administration in the fed state 
Part 3:  
Dolutegravir 50-mg tablet, oral administration in the fed state 
Duration of Study Intervention  
Part 1:  
S-648414 or matching placebo: single dose (1 day)  
Part 2:  
S-648414 or matching placebo: multiple doses (14 days) in Groups G and H 
Midazolam 5 mg on Day -2, S-648414 on Days 1 to 13, and S-648414 and midazolam 
5 mg coadministered on Day 14 


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Part 3:  
Multiple doses of dolutegravir once daily during Period 1 (7 days), multiple doses of 
S-648414 once daily during Period 2 (7 days), and multiple doses of S-648414 and 
dolutegravir 50 mg coadministered once daily during Period 3 (7 days) 
Study Duration for Individual Study Participants (Includes Screening, 
Treatment and Follow-up Period):  
Part 1:  
2 to 6 weeks (5 to 9 weeks for study participants in Group C) 
Part 2:  
4 to 8 weeks 
Part 3:  
5 to 9 weeks 
Data Monitoring Committee:  
No independent data monitoring committee will be established for this study. 
Prohibited Concomitant Therapy: 
Study participants must abstain from taking prescription or OTC drugs (including 
antacids, proton pump inhibitors, H2 antagonists, Chinese herbal medicines, oral 
cannabidiol, vitamins, minerals, herbal, and dietary supplements) within 14 days before 
the start of the first dose of study intervention (S-648414 or placebo) until completion of 
the Follow-up visit.  
In addition, from 28 days prior to admission to the completion of the study (including 
Follow-up period) the use of drugs or substances known to be inducers or inhibitors of 
cytochrome P450 enzymes and/or P-glycoprotein are prohibited. 
Concomitant therapies and medical procedures are prohibited during the study unless 
they are essential for the treatment of an AE: 
● From 14 days prior to admission to the completion of the study (including 
Follow-up period): the use of any therapies (prescribed or OTC drugs; antacids; 
proton pump inhibitors; H2 antagonists; and vitamins, minerals, herbal, and 
dietary supplements that have therapeutic effects), except for the study 
intervention (S-648414 or placebo) 
● During the study (admission to the completion of the study, including Follow-up 
period): medical procedures are prohibited unless essential for treatment of an 
AE. 


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Pharmacokinetic Assessments: 
Drug Concentration Measurements 
Blood and urine samples will be collected for analysis of plasma and urine S-648414 
concentrations.  
Pharmacokinetic Analyses 
Based on the plasma and urine concentrations of S-648414, the following PK parameters 
will be calculated:  
Part 1: 
Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), 
area under the concentration-time curve (AUC), terminal elimination half-life (t1/2,z), 
terminal elimination rate constant (λz), mean residence time (MRT), apparent total 
clearance (CL/F), apparent volume of distribution in the terminal elimination phase 
(Vz/F), renal clearance (CLR), and fraction of dose excreted in urine (Feu) 
Part 2: 
Based on the plasma concentrations of S-648414 and midazolam, the following PK 
parameters will be calculated:  
 S-648414: Cmax, Tmax, AUC over the dosing interval τ (AUC0-τ), CL/F, t1/2,z, λz, 
Vz/F, Feu over the dosing interval τ (Feu0-τ,), CLR 
 midazolam: Cmax, Tmax, AUC from time zero to the time of the last quantifiable 
concentration after dosing (AUC0-last), AUC extrapolated from time zero to 
infinity (AUC0-inf), t1/2,z, λz, and MRT 
Part 3: 
Based on the plasma concentrations of S-648414 and dolutegravir, the following PK 
parameters will be calculated:  
Cmax, Tmax, plasma concentration at the end of dosing interval τ (24 hours) (Cτ), AUC0-τ, 
and CL/F. 
Safety Assessments: 
Adverse events will be collected from the time of signing ICF to up to 10 days after the 
last dose of study intervention or last Follow-up visit. 
Additional safety assessments will include physical examinations, clinical laboratory tests 
(hematology, blood chemistry, and urinalysis), vital signs (systolic and diastolic blood 
pressure, pulse rate, respiratory rate, and body temperature), ophthalmological 
examinations, and 12-lead ECGs. 


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In addition, high-precision QTcF (Fridericia’s method) analysis using 12-lead ECG 
recording will be conducted from predose (Day 1) to 24 hours postdose (Day 2) in Part 1. 
A central ECG laboratory will extract ECG recording from the ECG device.  
Statistical Methods:  
Pharmacokinetics 
Part 1: 
Pharmacokinetic parameters will be calculated based on the plasma and urine 
concentrations of S-648414 by using the non-compartmental analysis. Dose 
proportionality, dose dependency, and food effect for S-648414 will be examined by 
using a power model or an analysis of variance (ANOVA). Further details on PK 
analyses will be included in a separate document. 
Part 2: 
Pharmacokinetic parameters will be calculated based on the plasma and urine 
concentrations of S-648414 by using the non-compartmental analysis. Dose 
proportionality, dose dependency, accumulation ratio, effect of multiple doses, and effect 
of S-648414 on midazolam PK will be examined by using an ANOVA. Further details on 
PK analyses will be included in a separate document. 
Part 3: 
The effects of S-648414 on the PK of dolutegravir and the effects of dolutegravir on the 
PK of S-648414 will be assessed by an ANOVA model. Further details on PK analyses 
will be included in a separate document. 
Safety 
The number of treatment-emergent AEs and the number of study participants who have 
experienced any treatment-emergent AEs will be summarized by treatment group. The 
summarization for treatment-related AEs will be performed in a similar manner. Physical 
examinations, ophthalmological examinations, clinical laboratory tests, vital signs, and 
12-lead ECGs will also be summarized. 
Cardiodynamic Electrocardiogram Evaluation 
The primary analysis will be based on concentration-QTc modeling of the relationship 
between the concentrations of S-648414 and change-from-baseline QTcF (∆QTcF) with 
the intent to exclude an effect > 10 msec at clinically relevant S-648414 plasma 
concentrations. In addition, the effect of S-648414 on the placebo-corrected ∆QTcF, 
ΔHR (heart rate), ΔPR, and ΔQRS (∆∆QTcF, ΔΔHR, ΔΔPR, and ΔΔQRS) will be 
evaluated at each postdosing time point (“by-time point” analysis) using the Intersection 
Union Test. An analysis of categorical outliers will be performed for changes in HR, PR, 
QRS, QTcF, T-wave morphology and U-wave presence.


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Table 1-5 
Sequence of Steps 
Group 
Sequence 
Part 1 – Single dosing after overnight fast of ≥ 10 hours 
Group A-1a 
(10 mg) 
Step 1-1 
 
 
 
 
 
 
 
 
 
 
Group A-2a 
(10 mg) 
 
Step 1-2 
 
 
 
 
 
 
 
 
 
Group B 
(30 mg) 
 
 
Step 2 
 
 
 
 
 
 
 
 
Group Cb 
(100 mg) 
 
 
 
Step 3-1 
Fasted 
Step 3-2 
Fed (30 minutes after the 
initiation of breakfast) 
 
 
 
 
 
Group D  
(250 mg) 
 
 
 
 
Step 4 
 
 
 
 
 
 
Group E  
(500 mg) 
 
 
 
 
 
Step 5 
 
 
 
 
 
Group F 
(1000 mg) 
 
 
 
 
 
 
Step 6 
 
 
 
 
Part 2– Multiple dosing administered 30 minutes after the initiation of breakfast 
 
 
Group G  
(50 mg)  
 
 
 
 
 
 
 
Step 7c 
MDZ 
 
 
 
Group H 
(30 mg)  
 
 
 
 
 
 
 
 
Step 8c 
MDZ 
 
 
Part 3 – Multiple dosing administered 30 minutes after the initiation of breakfast  
Group I 
(100 mg) 
 
 
 
 
 
 
 
 
 
Step 9d 
 
Group J 
(200 mg) 
 
 
 
 
 
 
 
 
 
 
Step 10d 


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MDZ = midazolam 
a 
The initial dose group (Group A) is divided into Group A-1 including 2 study participants (1 S-648414 and 1 placebo) and Group A-2 including 6 study 
participants (5 S-648414 and 1 placebo). Study participants in Group A-2 will receive study intervention (S-648414 or placebo) in a sentinel dosing 
sequence, ie, only after confirmation that there are no clinical concerns in Group A-1 within 24 hours postdose.  
b 
Group C-1 is the same as Step 3-1, and will be followed sequentially by Group C-2 (Step 3-2). For Group C, study participants will receive the first dose 
of study intervention (100 mg) in a fasted state (Group C-1), followed by a ≥ 14 days washout period and then the second dose of study intervention 
(100 mg) in a fed state (Group C-2). 
c 
Steps 7 and 8 will include administration of MDZ on Day -2 and Day 14 and multiple administrations of S-648414 or matching placebo. 
d 
Steps 9 and 10 will include administration of dolutegravir 50 mg once daily for 7 days, followed by a washout period of at least 7 days, followed by 
administration of S-648414 for 7 days, followed by coadministration of S-648414 and dolutegravir 50 mg once daily for 7 days. 
 


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1.2 
Schema 
See Schedule of Activities for Part 1 (Figure 1-2), Part 2 (Figure 1-3), and Part 3  
(Figure 1-4 and Figure 1-5). 
The study schematic in Part 3 is summarized below in Figure 1-1. 
Figure 1-1 
Study Schematic – Part 3 
Screening 
Period 
Period 1 
(Confinement 
in CRU) 
No Treatment  
Period 2 
(Confinement in 
CRU) 
Period 3 
(Confinement 
in CRU) 
Follow-up 
Period 
 
 
 
 
 
 
 
 
 
 
 
Dolutegravir 
QD 
No treatment 
S-648414 QD 
S-648414 QD 
+ dolutegravir 
QD 
 
 
 
 
 
 
 
 
 
 
4 weeks 
(Day -28 to 
Day -2) 
9 days 
(Day -1a to 
Day 8b) 
At least 5 days 
(Day 9 to 
Day 13)c 
8 days 
(Day 14d to 
Day 21) 
8 days 
(Day 22 to 
Day 29b) 
7 days 
after 
discharge 
of Period 3 
(Day 36) 
± 2 days 
CRU = clinical research unit; QD = once daily 
a 
Admission day is on Day -1; first day of dolutegravir is on Day 1. 
b 
Discharge from CRU (if applicable); no study intervention administered on day of discharge. 
c 
Study participant location (ie CRU or outpatient) will be at the discretion of the investigator. 
d 
Confinement in CRU starts on Day 14 and first day of S-648414 is Day 15. 
 
 






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BMI = body mass index; CRU = clinical research unit; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; PGx = pharmacogenomics; PK = pharmacokinetic 
a 
Study participants will be admitted to the CRU the day prior to the administration of study intervention (S-648414 or placebo) in the morning on Day -1 
and discharged on Day 5 after the completion of all study procedures.  
b 
Medical history includes a review of prior therapies (30 days prior to Screening visit). 
c 
Height will be measured only at Screening. 
d 
Vital signs include oral body temperature, pulse rate (1 measurement), respiratory rate, and blood pressure (3 consecutive readings) collected at 
Screening, Admission Day (Day -1), Day 1: predose (0 hours), 1.5, 3, 5, 8, and 12 hours postdose, Day 2: 24 hours postdose, Day 3: 48 hours postdose, 
Day 4: 72 hours postdose, Day 5: 96 hours postdose, and Follow-up (Days 8 to 12) or Early Termination visit. Allowable time frame for collection is 
± 20 minutes (2 to 0 hours for the predose collection).  
e 
Symptom-focused physical examinations include updates only. 
f 
Electrocardiograms for safety assessment at Screening, Admission Day (Day -1), Day 1: predose (0 hours), 1, 3, 5, and 12 hours postdose, Day 2: 
24 hours postdose, Day 5: 96 hours postdose, and Follow-up (Days 8 to 12) or Early Termination visit. Allowable time frame for collection is 
± 8 minutes (2 to 0 hours for the predose collection). 
g 
Cardiodynamic evaluations include High-precision 12-lead ECG tracings will be extracted from Holter recordings during the following time points: 
Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. For Group C, ECG will not be 
collected in Step 3-2. Electrocardiograms will be recorded after vital signs and prior to blood draws. Study participants will need to rest in the supine 
position for 10 minutes before and during the vital signs, ECGs, and blood draws and the rest must be documented in source notes. Allowable time frame 
for collection is ± 8 minutes (2 to 0 hours for the predose collection). 
h 
Ophthalmological assessments will be carried out by an ophthalmologist at the specified time points. 
i 
Additional data collection required for gastrointestinal adverse events: nausea, vomiting, diarrhea, and abdominal pain. 
j 
Serological tests include testing for positive syphilis, positive hepatitis B surface antigen, positive hepatitis C virus antibody, and positive HIV 
antigen/antibody. 
k 
Urine pregnancy test is only for females who are not diagnosed as postmenopausal. 
l 
Blood sample for serum FSH levels must be obtained to confirm female study participant’s postmenopausal status if there is no available documentation 
confirming postmenopausal status. 
m Laboratory tests include hematology, blood chemistry, and urinalysis. 
n 
Pharmacokinetic blood samples collected at predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose (Day 1), 24 hours postdose (Day 2), 
48 hours postdose (Day 3), 72 hours postdose (Day 4), and 96 hours postdose (Day 5). The PK blood sampling schedule may be changed according to the 
PK results in the preceding group(s). Allowable time frame for collection is ± 5 minutes, with the exception of the samples collected ≥ 24 hours postdose 
which is ± 30 minutes. 
o 
For study participants who agree to participate in the PGx research, these samples should be obtained on Admission Day (Day -1). 


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p 
Pharmacokinetic urine samples collected at predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose. The time 
intervals for urine sampling may be changed according to the PK results in the preceding group(s). 
q 
Metabolite profiling collected at predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose (Day 1), 24 hours postdose (Day 2), 48 hours 
postdose (Day 3), 72 hours postdose (Day 4), and 96 hours postdose (Day 5) for plasma samples. Metabolite profiling collected at predose (-12 to 
0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose for urine samples.  
r 
Study intervention (S-648414 or placebo) will be administered after an overnight fast of at least 10 hours. For group C, the second dose (Step 3-2) will be 
administered 30 minutes after the initiation of breakfast (high-fat meal). 
s 
For Group C, study participants will receive the first dose of study intervention (100 mg) in a fasted state (Group C-1), followed by a ≥ 14 days washout 
period and then the second dose of study intervention (100 mg) in a fed state (Group C-2). 
For the group of study participants who will be assessed for the effect of food (Group C), Step 3-1 and Step 3-2 study procedures will be started on Day -1.  
Unless otherwise stated, predose procedures will be completed within approximately 1 hour of dosing and approximately ± 10 minutes for all postdose 
procedures. 
 






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BMI = body mass index; CRU = clinical research unit; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; PGx = pharmacogenomics; PK = pharmacokinetic 
a 
Study participants will be admitted to the CRU the day prior to the administration of midazolam and discharged on Day 19 after the completion of all 
study procedures. 
b 
Medical history includes a review of prior therapies (30 days prior to Screening visit). 
c 
Height will be measured only at Screening. 
d 
Vital signs include oral body temperature, pulse rate (1 measurement), respiratory rate, and blood pressure (3 consecutive readings) collected at 
Screening, Admission Day (Day -3), Day -2: predose (0 hours) and 1.5 hours postdose, Day -1: Morning, Day 1: predose (0 hours), 0.5, 1.5, 3, 6, 8, and 
12 hours postdose, Day 2 to Day 13: predose (0 hours), Day 14: predose (0 hours), 1.5, 6, and 12 hours postdose, Day 15 to 18: Morning, Day 19: 
120 hours postdose (at discharge), and Follow-up (Day 23 to 27) or Early Termination visit. Allowable time frame for collection is ± 20 minutes (2 to 
0 hours for the predose collection).  
e 
Symptom-focused physical examinations include updates only. 
f 
Electrocardiograms for safety assessment at Screening, Admission Day (Day -3), Day -2: predose (0 hours), 1.5, 6, and 12 hours postdose, Day 1: 
predose (0 hours), 1.5, 6, and 12 hours postdose, Days 2, 5, 8, 11, and 14: predose (0 hours) and 1.5 hours postdose, Day 19:120 hours postdose (at 
discharge), Follow-up (Day 23 to 27) or Early Termination visit. Allowable time frame for collection is ± 8 minutes (2 to 0 hours for the predose 
collection). 
g 
Ophthalmological assessments will be carried out by an ophthalmologist at the specified time points. 
h 
Additional data collection required for gastrointestinal adverse events: nausea, vomiting, diarrhea, and abdominal pain. 
i 
Serological tests include testing for positive syphilis, positive hepatitis B surface antigen, positive hepatitis C virus antibody, and positive HIV 
antigen/antibody. 
j 
Urine pregnancy test is only for females who are not diagnosed as postmenopausal. 
k 
Blood sample for serum FSH levels must be obtained to confirm female study participant’s postmenopausal status if there is no available documentation 
confirming postmenopausal status. 
l 
Laboratory tests include hematology, blood chemistry, and urinalysis.  
m Pharmacokinetic blood samples collected at: 
 
Day -2 (midazolam): predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. 
 
Day 1 (S-648414): predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. 
 
Days 5, 7, 10, 12, and 13 (S-648414): predose (0 hours). 
 
Day 14 (midazolam): predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. 
 
Day 14 (S-648414): predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose. 
 
Allowable time frame for collection is ± 5 minutes and ≥ 24 hours after dosing is ± 30 minutes. 
n 
For study participants who agree to participate in the PGx research only, these samples should be obtained on Admission Day (Day -3). 


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o 
Pharmacokinetic urine sample collected on Day 14 only (0 to 24 hours postdose). 
p 
Biomarker sample collected on Day -2 and Day 14 (4 and 24 hours postdose). Allowable time frame for collection is ± 10 minutes, with the exception of 
the samples collected ≥ 24 hours after dosing which is ± 30 minutes. 
q 
The study intervention (S-648414 or placebo) will be administered 30 minutes after the initiation of breakfast. 
Unless otherwise stated, predose procedures will be completed within approximately 1 hour of dosing and approximately ± 10 minutes for all postdose 
procedures. 
 
 
 
 












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d 
Height will be measured only at Screening. 
e 
Vital signs include body temperature, pulse rate (1 measurement), respiratory rate, and blood pressure (3 consecutive readings) collected at Admission Day 
(Day 14), Days 15, 21, 22, and 28: predose, Day 29: 24 hours postdose, and Follow-up visit or Early Termination. Allowable time frame for collection is 
± 20 minutes (2 to 0 hours for the predose collection). 
f 
Symptom-focused physical examinations should be conducted for new or worsening adverse events/symptoms. 
g 
Electrocardiograms for safety assessment at Admission Day (Day 14), Days 15, 21, 22, and 28: predose, 1.5 hours postdose, Day 16: 24 hours postdose, 
Day 29 and Follow-up visit or Early Termination. Allowable time frame for collection is ± 8 minutes (2 to 0 hours for the predose collection). 
h 
Ophthalmological assessments will be carried out by an ophthalmologist at the specified time points. 
i 
Additional data collection required for gastrointestinal adverse events: nausea, vomiting, diarrhea, and abdominal pain. 
j 
Urine pregnancy test is only for females who are not diagnosed as postmenopausal. 
k 
Laboratory tests include hematology, blood chemistry, and urinalysis. 
l 
Pharmacokinetic blood samples collected.  
 
In Period 2, S-648414: Day 15: Pre-dose (0 hours), Day 18 to 20: Pre-dose (0 hours), Day 21: Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours 
postdose. 
 
In Period 3, S-648414 and dolutegravir: Day 22: Pre-dose (24 hours after Day 21 dose), Day 25 to 27: Pre-dose (0 hours), Day 28: Predose (0 hours), 0.5, 1, 
1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose (Day 29). 
 
Allowable time frame for collection is ± 5 minutes and ≥ 24 hours after dosing is ± 30 minutes. 
m Study intervention (S-648414) will be administered during Period 2 and study intervention (S-648414 and dolutegravir) will be administered during Period 3 
to study participants in a fed state (ie, 30 minutes after initiation of breakfast).  
Unless otherwise stated, predose procedures will be completed within approximately 1 hour of dosing and approximately ± 10 minutes for all postdose 
procedures. 
 
 


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2. INTRODUCTION 
2.1 
Study Rationale 
S-648414 is a novel antiretroviral agent that is being developed as a treatment for human 
immunodeficiency virus (HIV-1) infection in combination with other antiretroviral agents 
to fully suppress HIV-1 viremia. Based on a full pre-clinical development program of 
S-648414 this study is expected to be conducted safely and the minimum and maximum 
doses tested have been determined based on in-vitro efficacy estimations and animal 
Good Laboratory Practice (GLP)-compliant toxicology studies carried out to GLP 
standards. These Phase 1 assessments will describe the safety, tolerability, and 
pharmacokinetics (PK) of S-648414 following first-in-human dosing, both single 
ascending and multiple ascending dosing (SAD/MAD), food effect, effect on 
electrocardiogram (ECG) parameters, and effect on the PK of midazolam, a cytochrome 
P450 3A (CYP3A) probe, as well as the effect on PK of dolutegravir and the effect of 
dolutegravir on PK of S-648414. The study will permit evaluation of dosing and safety in 
the clinical setting to inform and facilitate studies in individuals living with HIV-1 
infection. 
2.2 
Background 
S-648414 inhibits HIV-1 replication via binding to a conserved allosteric pocket of the 
HIV-1 integrase (IN) enzyme known as an IN-lens epithelium-derived growth factor 
(LEDGF) binding pocket [1] and may cause abnormal IN multimerization resulting in 
inhibiting the viral particle maturation which is necessary for replication of HIV-1. This 
mechanism of action differs from all approved HIV treatments. 
HIV-1 infection, although incurable, can be effectively treated with combination 
antiretroviral therapy, usually consisting of 3 agents [2]. Combination antiretroviral 
therapy, when instituted early and with high levels of patient adherence, controls plasma 
viremia and leads to immune recovery with resulting reductions in morbidity and 
mortality [3]. A patient diagnosed early and treated effectively may have a normal life 
expectancy [4] and this treatment is also effective at preventing HIV transmission [5]. 
The efficacy of treatment may be compromised by reduced patient adherence, or the 
presence of preexisting antiretroviral resistance, which may be transmitted resistance [6] 
or reflect previous nonsuppressive/suboptimal therapy [7]. Some patients living with HIV 
were serially exposed to suboptimal therapy in the form of monotherapy or dual therapy 
as treatment paradigms evolved and new therapies became available. For these patients, 
efficacy of combination therapy instituted later was compromised by lack of sensitivity to 
some components of the regimen [8]. Reduced patient adherence can be driven by poor 
tolerability or toxicity problems with existing treatments [9]. Therefore, there is a need 
for new classes of antiretrovirals that overcome preexisting resistance and are better 
tolerated, with reduced pill burden and dosing frequency. 
Based on the nonclinical data obtained to date, S-648414 has shown comparable or better 
inhibitory effects on viral replication than those of other commercialized or 
investigational anti-HIV-1 drugs and no significant effect on various receptors, ion 
channels, transporters, or enzymes. S-648414 has also shown a largely good PK profile in 


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rats and monkeys. Radioactivity was detected in melanin-containing tissues (the choroid, 
ciliary body, and iris) at the final sampling time (840 hours postdose) in a pigmented rat 
quantitative whole-body autoradiography (QWBA) study; however, there was no toxic 
finding on eyes in 4-week toxicity studies in rats and monkeys. S-648414 was shown to 
be a substrate of P-glycoprotein and in vitro studies demonstrated an induction potential 
of cytochrome P450 (CYP) 1A2, CYP2B6, and CYP3A4. 
No safety concerns have arisen in the core battery of safety pharmacology studies. The 
potential of genotoxicity was considered low. In 2-week toxicity studies in rats treated 
with up to 300 mg/kg/day and monkeys treated with up to 1000 mg/kg/day, the target 
organs were the kidney, gastrointestinal (GI) tracts in rats and monkeys, and the liver in 
monkeys. In addition, slight prolongation of corrected QT interval (QTc) was also noted 
in monkeys at 1000 mg/kg/day. In 4-week toxicity studies in rats and monkeys treated up 
to 200 mg/kg/day, the adverse findings included infiltration of inflammatory cells and 
degeneration in the mucosa of the glandular stomach in rats and vomiting and increased 
plasma hepatobiliary parameters accompanied with hepatocellular vacuolation in 
monkeys. All of the findings showed reversibility after 4-week drug withdrawal. The no 
observed adverse levels (NOAEL) in rats and monkeys were estimated to be 
30 mg/kg/day (4.8 mg/kg as human equivalent dose [HED]) and 60 mg/kg/day 
(19.2 mg/kg as HED), respectively. From these data, it is considered that S-648414 has 
an acceptable safety profile for proceeding into clinical studies.  
This first-in-human Phase 1 study will assess the safety, tolerability, and PK of S-648414 
following both single ascending and multiple ascending dosing (SAD/MAD); it will also 
assess for a food effect, effect on ECG parameters, and effect on the PK of midazolam, a 
CYP3A probe. S-648414 will be administered as single oral doses up to 1000 mg and as 
repeated oral doses up to 50 mg once daily (QD) for 14 days. The study will also assess 
the safety and tolerability of multiple doses of S-648414 (100 mg and 200 mg) and the 
effect of these doses of S-648414 on the PK of dolutegravir and the effect of dolutegravir 
(50 mg) on the PK of S-648414. 
2.3 
Benefit/Risk Assessment 
S-648414 is an investigational agent and this study represents the first human exposure, 
Since S-648414 is intended as an antiretroviral agent for the treatment of HIV, there is no 
benefit for study participants. 
More detailed information about the potential risks and reasonably expected AEs of 
S-648414 may be found in the Investigator’s Brochure. 
 




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AUC = area under the concentration-time curve; Cτ = plasma concentration at the end of the dosing 
interval τ (24 hours); CL/F = apparent total clearance; CLR = renal clearance; Cmax = maximum plasma 
concentration; CYP3A = cytochrome P450 3A; ECG = electrocardiogram; Feu = fraction of dose 
excreted in urine; HR = heart rate; MDZ = midazolam; MRT = mean residence time; 
PK = pharmacokinetics; PR = measure between beginning of P wave until beginning of QRS complex; 
QRS = combination of the Q, R, and S waves; QTcF = Fridericia’s corrected QT; Tmax = time to 
maximum plasma concentration; t1/2,z = terminal elimination half-life; λz = terminal elimination rate 
constant; Vz/F = apparent volume of distribution in the terminal elimination phase; Δ = change from 
baseline; ΔΔ = placebo-corrected change from baseline 
4. STUDY DESIGN 
4.1 
Overall Design 
The study is a multicenter, randomized, double-blind (Parts 1 and 2) and open-label 
(Part 3), placebo-controlled, sequential group study in healthy adult study participants. 
The study consists of Part 1 (single ascending dose, food effect, and effects on ECG 
parameters including concentration-QTc analysis) and Part 2 (multiple dose and drug-
drug interaction with the CYP3A substrate), and Part 3 (the effect of S-648414 on the PK 
of dolutegravir and the effect of dolutegravir on the PK of S-648414). The sequence of 
steps in Parts 1, 2, and 3 are summarized in Table 6-3. 
Part 1: 
The study consists of a Screening period (Days −28 to −2), admission to the clinical 
research unit (CRU, Day −1), single administrations of S-648414 or matching placebo 
(Day 1), discharge from the CRU (Day 5), and a Follow-up visit (Day 10 ± 2) (see 
Figure 1-2). 
In Groups A, B, D, E, and F, eligible healthy adult study participants will be assigned to 
1 of 5 ascending dose groups (10 to 1000 mg) and receive a single oral dose of S -648414 
or placebo in a fasted state with 6 study participants per dose group receiving active drug 
and 2 study participants per dose group receiving placebo. Administration initiates from 
the lowest dose group, and the next group does not initiate until the Follow-up period has 
been completed for the previous group except for A-2 (see Table 4-1).  
In Group C, 8 study participants will be assigned to S-648414, and 2 study participants 
will be assigned to placebo. Study participants assigned to the 100-mg group will receive 
a single oral dose of S-648414 in a fasted state (Group C-1), followed by a single dose of 
S-648414 in a fed state (high-fat meal) (Group C-2). Each episode of dosing will be 
separated by a washout period of at least 14 days. 


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Table 4-1 
Part 1 Dose Groups 
Group Label 
S-648414 Dose 
Number of Active 
Study Participants 
Number of Placebo 
Study Participants 
Group A  
(Group A-1 and A-2)a 
10 mg 
6 
2 
Group B 
30 mg 
6 
2 
Group C  
(Group C-1 and C-2) 
100 mg 
8 
2 
Group D 
250 mg 
6 
2 
Group E 
500 mg 
6 
2 
Group F 
1000 mg 
6 
2 
a 
Because this is a first-in-human administration, the initial dose group (Group A) is divided into 
Group A-1 including 2 study participants (1 S-648414 and 1 placebo) and Group A-2 including 
6 study participants (5 S-648414 and 1 placebo). Study participants in Group A-2 will receive study 
intervention (S-648414 or placebo) in a sentinel dosing sequence, ie, only after confirmation that 
there are no clinical concerns in Group A-1 within 24 hours postdose. 
The doses may be changed depending on the results of the safety, tolerability, and PK in 
the preceding group(s), if necessary. The highest dose will not exceed 1000 mg. 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group. 
The next dose group will not be conducted if any of the following criteria are met: 
● Any study participant experiences a treatment-related SAE (ie, treatment-
emergent SAE considered related to the study intervention [S-648414 or placebo] 
by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
See Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of intensity 
(including HIV grading system), assessment of causality, and procedures for recording, 
evaluating, follow-up, and reporting. 
Part 2: 
Eligible healthy adult study participants are assigned to 1 of 2 dose groups (50 mg in 
Group G or 30 mg in Group H) and receive multiple oral doses of S-648414 tablet or 
placebo in a fed state with 8 study participants receiving active drug and 2 study 
participants receiving placebo per group (see Table 4-2). Administration of the next dose 
group (Group H) will not initiate until the Follow-up period has been completed for the 
previous group (Group G).  
In Groups G and H, the study consists of a Screening period (Days −28 to −4), 
admission to the CRU (Day −3), administration of midazolam 5 mg (Day −2 and Day 14) 


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and multiple administrations of S-648414 or matching placebo (Days 1 to 14), discharge 
from the CRU (Day 19), and a Follow-up visit (Day 25 ± 2) (see Figure 1-3). 
All study participants will receive a single oral dose of midazolam 5 mg alone on Day -2 
and coadministered with the S-648414/placebo dose on Day 14. Study participants will 
receive S-648414/placebo QD on Days 1 to 14 (Group G will receive 50 mg and Group H 
will receive 30 mg).  
Table 4-2 
Part 2 Dose Groups 
Group Label 
S-648414 Dose 
Number of 
Active Study 
Participants 
Number of 
Placebo Study 
Participants 
Length of 
Treatment 
(Days) 
Group G 
50 mg 
8 
2 
14 
Group H 
30 mg 
8 
2 
14 
 
The doses, mode of administration, frequency (ie, QD or twice daily [BID]), dietary 
condition (ie, fasted or fed), or length of administration may be changed depending on the 
results of the safety, tolerability, and PK in the preceding group(s), if necessary. 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group.  
The next dose group will not be conducted if any of the following criteria are met: 
● Any study participant experiences a treatment-related SAE (ie, treatment-
emergent SAE considered related to the study intervention [S-648414 or placebo] 
by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4treatment-related AEs 
See Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of intensity 
(including HIV grading system), assessment of causality, and procedures for recording, 
evaluating, and follow-up of AEs and SAEs, and reporting SAEs. 
Part 3: 
Part 3 is an open-label, non-randomized, 1-sequence, 3-period study.  
A total of 14 healthy adult study participants will be enrolled in Group I of Part 3; an 
additional 14 healthy adult study participants will be enrolled in Group J of Part 3. 
Part 3 will consist of: 
 Screening period (Days −28 to −2) 
 Period 1 (admission to CRU on Day -1 with continued confinement until Day 8) 


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 Mandatory 7-day washout between the last dose of study intervention in Period 1 
and the first dose of study intervention in Period 2 
o Day 8 of Period 1 (no dose) 
o Days 9 to 13 (5 days, no dose)  
The 5-day period can be inpatient or outpatient and will be decided at the 
discretion of the investigator. 
o Day 14 of Period 2 (no dose) 
 Period 2 (confinement: Days 14 to 21), 
 Period 3 (confinement: Days 22 to 29) 
 Follow-up visit (7 days after discharge from the CRU of Period 3 
[Day 36] ± 2 days) 
Study participants will receive: 
 Dolutegravir (50 mg orally QD for 7 days) in the fed state during Period 1 
 S-648414 alone (100 mg orally QD for 7 days in Group I or 200 mg orally QD for 
7 days in Group J) in the fed state during Study Period 2 
 S-648414 (100 mg orally QD for 7 days in Group I or 200 mg orally QD for 
7 days in Group J) coadministered with dolutegravir (50 mg orally QD for 7 days) 
in the fed state during Period 3 
See Table 4-3 for the treatment schedule and Figure 1-1 for the study schematic. 
Table 4-3 
Part 3 Treatment Schedule 
Group Label 
Number of 
Study 
Participants 
Period 1a 
Period 2a 
Period 3 
Group I 
14 
Dolutegravir 50 mg 
QD for 7 days 
S-648414 100 mg 
QD for 7 days 
S-648414 100 mg + 
dolutegravir 50 mg 
QD for 7 days 
Group J 
14 
Dolutegravir 50 mg 
QD for 7 days 
S-648414 200 mg 
QD for 7 days 
S-648414 200 mg + 
dolutegravir 50 mg 
QD for 7 days 
QD = once daily 
a 
There will be a 7-day washout period between Periods 1 and 2; the 7-day washout period includes 
the time when the study participant will not receive study intervention on the last day of Period 1 
and the first day of Period 2. 
The doses, mode of administration, frequency (ie, QD or BID), dietary condition (ie, 
fasted or fed), or length of administration may be changed by the sponsor depending on 
the results of the safety, tolerability, and PK in the preceding group(s), if necessary. 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group.  


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The next dose group will not be conducted if any of the following criteria are met: 
● Any study participant experiences a treatment-related SAE (ie, treatment-
emergent SAE considered related to S-648414 or by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
See Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of intensity 
(including HIV grading system), assessment of causality, and procedures for recording, 
evaluating, follow-up, and reporting. 
4.2 
Scientific Rationale for Study Design 
This Phase 1 study is designed to compare the PK, food effect, and effect on ECG 
parameters of single and multiple doses of S-648414 with placebo in a double-blind 
fashion. This is a first-in-human study and will begin with a single escalating dose to 
ensure safety and tolerability. The study will then progress to a multiple-dosing phase to 
further define PK parameters. The last phase of the study will include multiple dosing 
with and without dolutegravir to study effect of S-648414 on the PK of dolutegravir and 
the effect of dolutegravir on the PK of S-648414. 
4.3 
Justification for Dose 
In 4-week toxicity studies in rats and monkeys, the NOAELs were estimated to be 
30 mg/kg/day and 60 mg/kg/day and the HED was calculated as 4.8 mg/kg/day and 
19.2 mg/kg/day, respectively. Therefore, rats were used as the most sensitive species. 
The HED in rats was divided by a safety factor of 10 to calculate the maximum 
recommended starting dose (MRSD) as 0.48 mg/kg/day, which corresponds to 
28.8 mg/day assuming a body weight of approximately 60 kg in a healthy subject. 
The SAD segment of the study will evaluate S-648414 to investigate safety and PK 
profiles in healthy study participants. After review of the MRSD from the safety 
evaluation, 10 mg is proposed for the starting dose of S-648414.  
In this study, the dose will be increased up to 1000 mg as a single dose. A dose of 
1000 mg/human is near the NOAEL in the 4-week toxicity study in monkeys 
(60 mg/kg/day in monkeys, 1152 mg/human as the HED), and is greater than the NOAEL 
in the 4-week toxicity study in rats (30 mg/kg/day in rats, 288 mg/human as the HED). 
The toxic findings observed in the nonclinical toxicity studies were vomiting, GI mucosal 
irritation, increased plasma hepatobiliary parameters with hepatocellular vacuolation, and 
histopathological lesions in the kidneys with increased plasma creatinine and urea 
nitrogen; however, these findings were not life-threatening or irreversible and can be 
monitored by general clinical exams. The gastric mucosal irritation, the most sensitive 
AE in the 4-week toxicity study in rats, was considered to be related to local exposure 
rather than systemic exposure; therefore, the planned maximum single dose in the SAD 
segment of the study is considered to be below the NOAEL in the 4-week toxicity study 


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in rats (1800 mg/human/day as human mg/kg equivalent dose assuming a body weight of 
approximately 60 kg in a healthy subject). Study participants will be closely monitored 
for events prior to escalating doses; therefore, it is justifiable to dose study participants up 
to 1000 mg in this study. 
The MAD segment of the study will evaluate QD dosing of S-648414 for 14 days. The 
initial planned dose in the MAD segment of the study is 50 mg/day and the subsequent 
dose is 30 mg/day. Administration of 50 mg/day in the multiple-dose cohort will begin 
after review of safety data obtained from the 1000 mg/day single-dose cohort. If safety 
concerns are raised in the single-dose portion, the doses for MAD segment may be 
modified.  
Part 3 of the study will evaluate the drug-interaction between S-648414 and dolutegravir. 
The treatment schedule, including the washout period, are defined based on the terminal 
elimination half-life of dolutegravir (approximately 14 hours) (see dolutegravir package 
insert [11]) and S-648414 (expected to be < 24 hours). The dose of dolutegravir to be 
used in this study is set in accordance with the approved dosage and administration of 
dolutegravir (see dolutegravir package insert [11]). If safety concerns are raised in the 
single-dose portion, the doses for Part 3 may be modified. 
After reviewing unblinded safety data from the 50 mg multiple dose group, it was 
determined that it is acceptable to increase the dose to 100 mg. The initial planned dose 
in Part 3 is 100 mg/day and the subsequent dose is 200 mg/day. Administration of 
200 mg/day in the multiple-dose cohort will begin after review of safety data obtained 
from the 100 mg/day in Part 3.  
4.4 
End of Study Definition 
A study participant is considered to have completed the study if he/she has completed all 
periods of the study including the last visit. 
The end of the study is defined as the date of the last visit of the last study participant in 
the study.  
5. STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Study participants are eligible to be included in the study only if all of the following 
criteria apply:  
1. Male or female adults ≥ 18 years in USA or ≥ 20 years in Japan to ≤ 55 years of 
age, at the time of signing the informed consent form (ICF). 
a) Specific to Japan sites: enrollment in Part 3 (Group I and J) will consist of 
only White or Black or African American race. 


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2. Capable of giving signed informed consent as described in Section 10.1 
(Appendix 1), which includes compliance with the requirements and restrictions 
listed in the ICF and in this protocol. 
3. Body mass index (BMI) ≥ 18.5 to < 32.0 kg/m2 at the Screening visit． 
4. Considered medically healthy as determined by the investigator or subinvestigator 
(suitably qualified), based on medical history and clinical evaluations including 
physical examination, clinical laboratory tests, vital sign measurements, and 
12-lead ECG at Screening and at upon admission to the CRU and prior to 
administration of study intervention on Day 1. Clinical evaluations during 
Screening can be repeated (for confirmatory purposes or if additional information 
is required to assess study participant’s eligibility) at the discretion of the 
investigator; repeated procedures must be performed within the same Screening 
window.  
5. Female study participants must not be a woman of childbearing potential (see 
Section 10.4 [Appendix 4]) and must either be postmenopausal (defined as no 
menses for 12 months without an alternative medical cause; follicle-stimulating 
hormone (FSH) to be tested for confirmation at Screening) or premenopausal with 
1 of the following documented: hysterectomy, tubal ligation, bilateral 
salpingectomy, or bilateral oophorectomy. 
6. Male study participants must agree to use contraception as detailed in 
Section 10.4 (Appendix 4) during the treatment period and for at least 3 months 
after the last dose of study intervention.  
5.2 
Exclusion Criteria  
Study participants are excluded from the study if any of the following criteria apply:  
Medical Conditions 
1. Considered by the investigator or subinvestigator (suitably qualified) to be 
ineligible for the study due to a history of or current condition of significant 
metabolic or endocrine, hepatic, renal, hematological, pulmonary, cardiovascular, 
GI, urological, immunological, neurological, or psychiatric disorders with clinical 
manifestations.  
2. History or presence of cancer in last 5 years except for nonmelanoma skin 
cancers.  
3. Risk factors for:  
a. Torsades de Pointes (eg, heart failure, cardiomyopathy, or family history of 
Long QT Syndrome or Brugada Syndrome) 
b. Unexplained syncope, sick sinus syndrome, second- or third-degree 
atrioventricular (AV) block, myocardial infarction, pulmonary congestion, 
cardiac arrhythmia, angina, prolonged QT interval, or conduction 
abnormalities  
4. History of GI surgery or disease including, but not limited to, gastric band/gastric 
resection and/or intestinal resection and/or duodenal disease (ie, celiac disease) 


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that may result in clinically significant malabsorption (except for an 
appendectomy). 
5. History of hypersensitivity or severe side effects induced by a drug.  
6. Any condition requiring medication and/or other treatment, such as dietary 
restriction and physical therapy.  
7. History of significant multiple and/or severe allergic symptoms including food 
allergy (NOTE: Study participants with seasonal allergies may participate unless 
they have ongoing symptoms).  
Prior/Concomitant Therapy 
8. Used drugs or substances known to be inducers or inhibitors of cytochrome P450 
enzymes and/or P-glycoprotein within 28 days prior to admission to the CRU. 
9. Used prescription or over-the-counter (OTC) drugs, antacids, proton pump 
inhibitors, H2 antagonists, Chinese herbal medicines, oral cannabidiol, vitamins, 
minerals, herbal, and dietary supplements within 14 days prior to admission to the 
CRU. 
Caffeine, Alcohol, Recreational Drugs, and Tobacco or Nicotine 
10. Refuses to abstain from ingesting caffeine- or xanthine-containing 
products/medications (eg, coffee, tea, cola drinks, other caffeinated beverages, or 
chocolate) from 24 hours prior to admission to the CRU or refuses to refrain from 
consuming such products throughout the study (including Follow-up period). 
11. Consumed alcohol or used alcohol-containing products within 72 hours prior to 
admission to the CRU or refuses to refrain from consuming such products 
throughout the study (including Follow-up period).  
12. History of recreational drug use in the previous 6 months or has a history of 
problematic alcohol use (defined as study participants who regularly consume 
excessive amounts of alcohol, defined as > 3 glasses of alcoholic beverages per 
day (1 glass is approximately equivalent to: beer [284 mL/10 ounces (oz.)], wine 
[125 mL/4 oz.] or distilled spirits [25 mL/1 oz.]).  
13. A positive drug or alcohol screen at the Screening visit or upon admission to the 
CRU. 
14. Used tobacco- or nicotine-containing products (including cigarette, pipe, cigar, 
chewing, nicotine patch, or nicotine gum) within 6 months prior to admission to 
the CRU or refuses to refrain from using tobacco- or nicotine-containing products 
throughout the study (including Follow-up period). 
Meals and Dietary Restrictions 
15. Consumed grapefruit, grapefruit juice, Seville orange juice, orange juice, apple 
juice, vegetables from the mustard green family (eg, kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels sprouts, mustard greens), or charbroiled meats 
within 7 days prior to admission to the CRU or refuses to refrain from consuming 
such products throughout the study (including Follow-up period).  


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Diagnostic Assessments 
16. A corrected QT (QTc) interval of > 450 msec for males and > 470 msec for 
females (Fridericia’s method) at the Screening visit or upon admission to the 
CRU. 
17. Systolic blood pressure is outside the range of 90 to 140 mm Hg, diastolic blood 
pressure is outside the range of 50 to 90 mm Hg, or pulse rate is outside the range 
of 40 to 100 beats per minute (bpm) or considered ineligible by the investigator or 
subinvestigator at the Screening visit or upon admission to the CRU. 
18. Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase 
(AST) values are greater than the upper limit of normal (ULN) or estimated 
glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 at Screening or upon 
admission to the CRU. 
19. A positive serological test for untreated syphilis, positive hepatitis B surface 
antigen, positive hepatitis C virus antibody, or positive human immunodeficiency 
virus (HIV) antigen/antibody result at the Screening visit.  
Prior/Concurrent Clinical Study Experience 
20. Participated in any other investigational trials or has been exposed to other 
investigational drugs within 28 days or 5 half-lives of the previously administered 
investigational drug (date derived from last study procedure [blood collection or 
dosing] of previous trial), whichever is longer, prior to admission to the CRU.  
21. Previously received S-648414. 
Other Exclusions 
22. Poor venous access. 
23. Donated blood (> 500 mL) or had significant blood loss within 56 days of study 
admission to the CRU or donated plasma within 7 days prior to until admission to 
the CRU.  
24. Considered inappropriate for participation in the study for any reason by the 
investigator or subinvestigator. 
5.3 
Lifestyle Considerations 
Lifestyle considerations (including use of caffeine, alcohol, recreational drugs, and 
tobacco or nicotine and meals and dietary restriction) are included in the exclusions in 
Section 5.2. 
5.3.1 
Meals and Dietary Restrictions 
Meals and dietary restrictions are described in exclusion criterion 15 and further 
discussed below: 
1. Water will be allowed at all times except for 1 hour prior to administration of 
study intervention. See Table 6-1 for water requirements during administration of 
study intervention. 


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2. During site stay, all foods/beverages will be provided by the medical institution 
and study participants in the same treatment step (see Table 6-3) will be given the 
same meals (2000 to 2500 kcal per day, except for the days of admission and 
administration of study intervention) except for Step 3-2. From consent 
acquisition to the completion of the end-of-study (or early termination) 
examination, study participants must refrain from excess eating and excess 
drinking. 
3. In each treatment step (see Table 6-3), except for Step 3-2, Steps 7, 8, 9, and 10, 
study participants will fast from all food and beverages, except water, for at least 
10 hours prior to administration of study intervention. No food should be allowed 
for at least 4 hours postdose. 
4. Study participants in Step 3-2 will fast from all food and beverages, except water, 
for at least 10 hours prior to consuming a high-fat, high-calorie breakfast. Study 
participants should be encouraged to consume the entire meal and within 
≤ 30 minutes of starting. Study intervention will be administered 30 minutes after 
the start of the consumption of the meal. The breakfast will consist of a high-fat 
(approximately 50% of total caloric content of the meal) and high-calorie 
(approximately 800 to 1000 calories) meal with approximately 150, 250, and 500 
to 600 calories from protein, carbohydrate, and fat, respectively (eg, 2 eggs fried 
in butter, 2 strips of bacon, 2 slices of toast with butter, 4 oz. of hash brown 
potatoes, and 8 oz. of whole milk). No food should be allowed for at least 4 hours 
postdose. 
5. Study participants in Steps 7, 8, 9, and 10 will receive study intervention 
30 minutes following consumption of a standardized breakfast. No food should be 
allowed for at least 4 hours postdose. 
Caffeine, alcohol, recreational drugs, and tobacco or nicotine restrictions are described in 
exclusion criteria 10 through 14. 
5.3.2 
Activity 
Study participants will be instructed to refrain from strenuous physical activity that could 
cause muscle aches or injury, including contact sports or heavy lifting, at any time from 
the Screening visit and throughout the study until the last outpatient visit. 
5.4 
Screen Failures 
Screen failures are defined as study participants who consent to participate in the clinical 
study but are not subsequently exposed to study intervention (S-648414 or placebo). 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 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE. 


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6. STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to, or used by, a study 
participant according to the study protocol. 
The study interventions in this study are summarized in Table 6-1 and the number of 
tablets per dose group is summarized in Table 6-2. 
6.1 
Study Intervention(s) Administered 
Table 6-1 
Study Intervention(s) 
Study Intervention 
Name: 
S-648414 
Placebo 
Midazolam 
Dolutegravira 
Dosage 
formulation: 
Tablet 
Tablet 
Oral 
suspension 
Tablet 
Unit dose 
strength(s)/Dosage 
level(s): 
Unit dose: 10 mg 
and 100 mg 
Dosage levels: 
10 mg, 30 mg, 
50 mg, 100 mg, 
200 mg, 250 mg, 
500 mg, 1000 mg 
Unit dose: 10 mg 
and 100 mg 
Dosage levels: 
10 mg, 30 mg, 
50 mg, 100 mg, 
250 mg, 500 mg, 
1000 mg 
Unit dose: 
2 mg/mL) 
Dosage 
level: 5 mg 
50 mg 
Physical 
description: 
10 mg tablets: 
6 mm white 
round tablets 
 
100 mg tablets: 
9 mm white 
round tablets 
10 mg tablets:  
6 mm white 
round tablets 
 
100 mg tablets: 
9 mm white 
round tablets 
Red or 
pinkish oral 
solution 
Yellow round 
tablets 
Route of 
administration:  
Oral 
Oral 
Oral 
Oral 
Dosing instructions: 
Administer 
240 mL water 
during 
administration 
 
Part 1: fasted or 
fed state 
Part 2: fed state 
Part 3: Periods 2 
and 3 in fed state 
See Section 5.3.1 
for timing of food 
 
See number of 
tablets per dose 
group in 
Table 6-2 
Administer 
240 mL water 
during administration 
 
Part 1: fasted or fed 
state 
Part 2: fed state 
See Section 5.3.1 for 
timing of food 
 
See number of 
tablets per dose 
group in Table 6-2 
Fed state 
See 
Section 5.3.1 
for timing of 
food 
Administer 
240 mL water 
during 
administration 
 
Part 3: Periods 1 
and 3: fed state: 
See Section 5.3.1 
for timing of food 


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Study Intervention 
Name: 
S-648414 
Placebo 
Midazolam 
Dolutegravira 
Packaging and 
labeling: 
Provided in 
HDPE bottle with 
desiccant, 
1 bottle per box. 
Each bottle and 
box will be 
labeled as 
required per 
country 
requirement. 
Provided in HDPE 
bottle with desiccant, 
1 bottle per box. 
Each bottle and box 
will be labeled as 
required per country 
requirement. 
Provided in 
glass bottle 
Provided in bottle 
with desiccant 
Manufacturer: 
Shionogi Pharma 
Shionogi Pharma 
Perrigo or 
generic 
equivalent 
ViiV 
Shelf Life: 
Upon opening the 
bottle, tablets 
must be used 
within 7 days. 
Upon opening the 
bottle, tablets must 
be used within 
7 days. 
As described 
on bottle. 
As described on 
bottle. 
HDPE = high-density polyethylene 
a 
For further information on dolutegravir, refer to Package Insert [11] 
(https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing Information/Ti
vicay/pdf/TIVICAY-PI-PIL.PDF#page=1 and 
https://gskpro.com/content/dam/global/hcpportal/ja JP/products-info/viiv/tivicay/tivicay.pdf) 
 
Table 6-2 
Number of Tablets (S-648414 or Placebo) per Dose Group 
Dose (mg) 
10 mg Tablet 
100 mg Tablet 
10 
1 
0 
30 
3 
0 
50 
5 
0 
100 
0 
1 
200 
0 
2 
250 
5 
2 
500 
0 
5 
1000 
0 
10 
 
6.2 
Preparation/Handling/Storage/Accountability of Study 
Intervention 
1. Study intervention should be kept at room temperature (15ºC to 30ºC).  
2. The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
3. Only study participants enrolled in the study may receive study intervention and 
only authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and 


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monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
4. The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (ie, receipt, study participant dispensation, reconciliation, and 
final disposition records). 
5. Final disposition of unused study intervention will be performed by the study site 
according to the site’s standard operating procedure (SOP) upon written approval 
from the sponsor.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
A randomized list will be produced by an unblinded statistician and provided to the 
unblinded site pharmacist, who will dispense study intervention (S-648414 or placebo) 
based on the provided list. Before the study is initiated, instructions will be provided to 
the study personnel.  
Once a randomization number has been assigned, it must not be re-assigned. 
Study intervention will be dispensed at the study visits summarized in the Schedule of 
Activities (Part 1 in Figure 1-2, Part 2 in Figure 1-3, and Part 3 in Figure 1-4 and  
Figure 1-5). 
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a study participant’s treatment assignment is warranted. Study participant 
safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator should make every 
effort to contact the sponsor prior to unblinding a study participant’s treatment 
assignment unless this could delay emergency treatment of the study participant. Once it 
is determined to unblind, the investigator should contact the site pharmacist who can 
break the blind. If a study participant’s treatment assignment is unblinded, the sponsor 
must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and electronic case 
report forms (eCRF) as applicable. 
6.4 
Study Intervention Compliance 
Study intervention dosing will be observed and recorded in the eCRF. Any study 
intervention refused, or if the study participant vomits within 1 hour of dosing, will also 
be recorded in the eCRF. The time of vomiting in relation to dosing will be recorded. 
6.5 
Prior Therapy/Concomitant Therapy 
Participants must abstain from taking prescription or OTC drugs (including vitamins and 
dietary or herbal supplements) within 14 days before the start of first dose of study 
intervention (S-648414 or placebo) until completion of the Follow-up visit.  


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In addition, from 28 days prior to admission to the completion of the study (including 
Follow-up period) the use of drugs or substances known to be inducers or inhibitors of 
cytochrome P450 enzymes and/or P-glycoprotein are prohibited. 
Concomitant therapies and medical procedures are prohibited during the study unless 
they are essential for the treatment of an AE: 
● From 14 days prior to admission to the completion of the study (including 
Follow-up period): the use of any therapies (prescribed or OTC drugs; antacids; 
proton pump inhibitors; H2 antagonists; and Chinese herbal medicines, oral 
cannabidiol, vitamins, minerals, herbal, and dietary supplements that have 
therapeutic effects) except for the study intervention (S-648414 or placebo). 
● During the study (admission to the completion of the study, including Follow-up 
period): medical procedures are prohibited unless essential for treatment of an 
AE. 
The medical monitor should be contacted if there are any questions regarding prior or 
concomitant therapy. 
6.6 
Dose Modification of Study Intervention 
The sequence of steps in Part 1 (SAD), Part 2 (MAD) and Part 3 (MAD with 
dolutegravir) is summarized in Table 6-3.


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Table 6-3 
Sequence of Steps 
Group 
Sequence 
Part 1 – Single dosing after overnight fast of ≥ 10 hours 
Group A-1a 
(10 mg) 
Step 1-1 
 
 
 
 
 
 
 
 
 
 
Group A-2a 
(10 mg) 
 
Step 1-2 
 
 
 
 
 
 
 
 
 
Group B 
(30 mg) 
 
 
Step 2 
 
 
 
 
 
 
 
 
Group Cb 
(100 mg) 
 
 
 
Step 3-1 
Fasted 
Step 3-2 
Fed (30 minutes after the 
initiation of breakfast) 
 
 
 
 
 
Group D  
(250 mg) 
 
 
 
 
Step 4 
 
 
 
 
 
 
Group E  
(500 mg) 
 
 
 
 
 
Step 5 
 
 
 
 
 
Group F 
(1000 mg) 
 
 
 
 
 
 
Step 6 
 
 
 
 
Part 2 – Multiple dosing administered 30 minutes after the initiation of breakfast 
 
 
Group G  
(50 mg)  
 
 
 
 
 
 
 
Step 7c 
MDZ 
 
 
 
Group H 
(30 mg)  
 
 
 
 
 
 
 
 
Step 8c 
MDZ 
 
 
Part 3 – Multiple dosing administered 30 minutes after the initiation of breakfast 
Group I 
(100 mg) 
 
 
 
 
 
 
 
 
 
Step 9d 
 
Group J 
(200 mg) 
 
 
 
 
 
 
 
 
 
 
Step 10d 


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MDZ = midazolam 
a 
The initial dose group (Group A) is divided into Group A-1 including 2 study participants (1 S-648414 and 1 placebo) and Group A-2 including 6 study 
participants (5 S-648414 and 1 placebo). Study participants in Group A-2 will receive study intervention (S-648414 or placebo) in a sentinel dosing 
sequence, ie, only after confirmation that there are no clinical concerns in Group A-1 within 24 hours postdose.  
b 
Group C-1 is the same as Step 3-1, and will be followed sequentially by Group C-2 (Step 3-2). For Group C, study participants will receive the first dose 
of study intervention (100 mg) in a fasted state (Group C-1), followed by a ≥ 14 days washout period and then the second dose of study intervention 
(100 mg) in a fed state (Group C-2). 
c 
Steps 7 and 8 will include administration of MDZ on Day -2 and Day 14 and multiple administrations of S-648414 or matching placebo. 
d 
Steps 9 and 10 will include administration of dolutegravir 50 mg once daily for 7 days, followed by a washout period of at least 7 days, followed by 
administration of S-648414 for 7 days, followed by coadministration of S-648414 and dolutegravir 50 mg once daily for 7 days. 
 


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6.6.1 
Part 1 – Single Dosing 
In Groups A, B, D, E, and F, eligible healthy adult study participants will be assigned to 
1 of 5 ascending dose groups (10 to 1000 mg) and receive a single oral dose on Day 1 of 
S -648414 or placebo in a fasted state with 6 study participants per dose group receiving 
active drug and 2 study participants per dose group receiving placebo (see Table 4-1). 
Administration initiates from the lowest dose group and the next group does not initiate 
until the Follow-up period has been completed for the previous group except for A-2. 
In Group C, 8 study participants will be assigned to S-648414 and 2 study participants 
assigned to placebo. Study participants assigned to the 100-mg group will receive a single 
oral dose of S-648414 in a fasted state (Group C-1), followed by a single dose of 
S-648414 in a fed state (high-fat meal) (Group C-2). Each episode of dosing will be 
separated by a washout period of at least 14 days. 
The doses may be changed depending on the results of the safety, tolerability, and PK in 
the preceding group(s), if necessary. The highest dose will not exceed 1000 mg. 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group. 
The next dose group will not be conducted if any of the following criteria are met: 
● Any study participant experiences a treatment-related SAE (ie, treatment-
emergent SAE considered related to the study intervention [S-648414 or placebo] 
by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
6.6.2 
Part 2 – Multiple Dosing 
In Groups G and H, all study participants will receive a single oral dose of midazolam 
5 mg alone on Day -2 and Day 14. In Group G, 8 study participants will be assigned to 
S-648414 (50 mg QD from Day 1 to Day 14) and 2 study participants to placebo (daily 
from Day 1 to Day 14). In Group H, 8 study participants will be assigned to S-648414 
(30 mg QD from Day 1 to Day 14) and 2 study participants to placebo (daily from Day 1 
to Day 14). Study participants will receive study intervention (S-648414 or placebo) 
30 minutes after the initiation of breakfast.  
The doses, mode of administration, frequency (ie, QD or BID), dietary condition 
(ie, fasted or fed), or length of administration may be changed depending on the results of 
the safety, tolerability, and PK in the preceding group(s), if necessary. 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group.  
The next dose group will not be conducted if any of the following criteria are met: 


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● Any study participant experiences a treatment-related SAE (ie, treatment-
emergent SAE considered related to the study intervention [S-648414 or placebo] 
by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
6.6.3 
Part 3 – Coadministration with Dolutegravir 
In Groups I and J, study participants will receive dolutegravir (50 mg orally QD for 
7 days) during Period 1, followed by no treatment for at least 7 days, followed by 
S-648414 for 7 days during Period 2, followed by coadministration of S-648414 and 
dolutegravir 50 mg QD for 7 days during Period 3.  
Group I will receive 100 mg of S-648414 and Group J will receive 200 mg of S-648414. 
A total of 14 healthy adult study participants will be enrolled in Group I of Part 3; an 
additional 14 healthy adult study participants will be enrolled in Group J of Part 3.  
The dose, mode of administration, frequency (ie, QD or twice daily [BID]), dietary 
condition (ie, fasted or fed), or length of administration may be changed, if necessary, by 
the sponsor depending on the results of the safety, tolerability, and PK in the preceding 
group(s). 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group.  
The next dose group will not be conducted if any of the following criteria are met: 
● Any study participant experiences a treatment-related SAE (ie, treatment-
emergent SAE considered related to S-648414 by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
See Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of intensity 
(including HIV grading system), assessment of causality, and procedures for recording, 
evaluating, follow-up, and reporting. 
6.7 
Intervention After the End of the Study 
This is a Phase 1 study; therefore, there is no study intervention following the end of the 
study. 


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7. DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Intervention 
Part 1 is single dosing; therefore, discontinuation of study intervention is not applicable. 
Part 2 and Part 3 are multiple dosing; therefore, the following applies only to Part 2 and 
Part 3: 
Study participants will be discontinued from study intervention if the study participant 
requests to discontinue study intervention, but should be encouraged to remain in study 
for safety monitoring. If a study participant withdraws consent from any further 
intervention in the study, they will be discontinued.  
See the Schedule of Activities for Part 2 (Figure 1-3) and for Part 3 (Figure 1-4 and 
Figure 1-5) for data to be collected at the time of discontinuation of study intervention 
and follow-up and for any further evaluations that need to be completed. 
If a study participant discontinues from the study during Part 3, a replacement study 
participant may be enrolled if deemed appropriate by the sponsor. 
7.1.1 
Discontinuation of Study Intervention for Abnormal Liver 
Function 
Discontinuation of study intervention for abnormal liver function should be considered 
by the investigator when a study participant meets 1 of the following conditions: 
 ALT ≥ 3 x ULN 
 The investigator believes that it is in best interest of the study participant  
 If ALT ≥ 3 x ULN and bilirubin ≥ 2 x ULN (> 35% direct bilirubin) or INR > 1.5, 
report as a SAE (see Section 10.6 [Appendix 6]) 
Further details on liver chemistry stopping criteria and follow-up assessments can be 
found in Section 10.6 (Appendix 6). 
7.1.2 
Discontinuation of Study Intervention for Cardiac Changes 
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the 
investigator or qualified designee will determine if the participant can continue in the 
study and if any change in participant management is needed. This review of the ECG 
printed at the time of collection must be documented. Any new clinically relevant finding 
should be reported as an AE. 
7.1.3 
Discontinuation of Study Intervention for Pregnancy 
As discussed in Section 8.3.5, if a female study participant becomes pregnant during the 
study, the investigator (or subinvestigator) will immediately discontinue study 


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intervention. Further details on collection of pregnancy information are summarized in 
Section 10.4 (Appendix 4).  
7.2 
Study Participant Discontinuation/Withdrawal from the Study 
A study participant may withdraw from the study at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. However, unless there is a safety reason, the study 
participant should remain in the trial even while off drug to protect the integrity of the 
study. 
If the study participant withdraws consent, the sponsor may retain and continue to use 
any data collected before the withdrawal of consent. 
If a study participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
See the Schedule of Activities (Part 1 in Figure 1-2, Part 2 in Figure 1-3, and Part 3 in 
Figure 1-4 and Figure 1-5) for data to be collected at the time of study discontinuation 
and follow-up and for any further evaluations that need to be completed. 
7.3 
Lost to Follow-up 
A study participant will be considered lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the site staff.  
The following actions must be taken if a study participant fails to return to the clinic for a 
required study visit: 
 The site staff must attempt to contact the study participant and reschedule the 
missed visit as soon as possible, counsel the study participant on the importance 
of maintaining the assigned visit schedule, and ascertain whether or not the study 
participant wishes to and/or should continue in the study. 
 Before a study participant is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the study participant by 
phone and the contact attempts should be documented in the study participant’s 
medical record. 
 Should the study participant continue to be unreachable, he/she will be considered 
to have withdrawn from the study.  


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8. STUDY ASSESSMENTS AND PROCEDURES 
 Study procedures and their timing are summarized in the Schedule of Activities 
(Part 1 in Figure 1-2, Part 2 in Figure 1-3, and Part 3 in Figure 1-4 and  
Figure 1-5). 
 Protocol waivers or exemptions are not allowed. 
 Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
 Adherence to the study design requirements, including those specified in the 
Schedule of Activities, is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that 
potential study participants meet all eligibility criteria. The investigator must 
maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable (see 
Section 5.4).  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1 
Efficacy Assessments  
Not applicable. 
8.2 
Safety Assessments  
Planned time points for all safety assessments are provided in the Schedule of Activities. 
(Part 1 in Figure 1-2, Part 2 in Figure 1-3, and Part 3 in Figure 1-4 and Figure 1-5). 
Unless otherwise stated in the Schedule of Activities (Part 1 in Figure 1-2, Part 2 in 
Figure 1-3, and Part 3 in Figure 1-4 and Figure 1-5), predose procedures will be 
completed within approximately 1 hour of dosing and approximately ± 10 minutes for all 
postdose procedures 
For any abnormal laboratory test results (hematology, blood chemistry, or urinalysis) or 
other safety assessments (eg, physical examination, ophthalmological examination, vital 
signs, ECGs) that worsen following exposure to the study intervention from baseline, the 
investigator will consider whether those results are clinically significant. Abnormal 
laboratory (including urine) test results are defined as values outside the reference range. 
For test results that are abnormal at baseline and significantly worsen following the 
initiation of the study, the investigator must also consider whether those results are 
clinically significant. Any test results that are considered clinically significant by the 
investigator are to be recorded as AEs. If the abnormal laboratory finding is associated 
with disease or organ toxicity, the investigator should report only the disease or organ 
toxicity as an AE. 
The investigator will consider test results to be clinically significant in the following 
circumstances (at their own discretion in the other circumstances): 


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● Test results that lead to any of the outcomes included in the definition of an SAE 
(See Section 8.3). 
● Test results that lead to a change in study intervention dosing or discontinuation 
from the study. 
● Test results that lead to a concomitant drug treatment or other therapy. 
● Test results that require additional diagnostic testing (except for a confirmatory 
test) or other medical intervention. 
● Test results that meet the management and discontinuation criteria for abnormal 
liver function tests identified in Section 7.1 and Section 10.6 (Appendix 6). 
In addition, when any test result meets the management and discontinuation criteria for 
liver function abnormalities (Section 7.1 and Section 10.6 [Appendix 6]), the results of 
further assessments and required follow-up should be recorded in the Liver Event Form. 
8.2.1 
Physical Examinations 
 A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, GI, and neurological systems. Height and weight will 
also be measured and recorded. Complete physical examinations will be 
performed at visits specified in Section 1.3. 
 A symptom-focused physical examination relevant to the study participant’s 
current condition will be performed as clinically indicated at visits specified in 
Section 1.3 for new or worsening adverse events/symptoms. 
 Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.2 
Vital Signs 
 Body temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed. 
 Blood pressure and pulse measurements will be assessed in the supine position, 
with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
 Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (eg, television, cell 
phones). This needs to be documented in source notes.  
 Vital signs (to be taken before blood collection for laboratory tests) will consist of 
1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute). Each of the 3 blood 
pressure readings will be recorded on the eCRF. 
8.2.3 
Electrocardiograms 
 A triplicate 12-lead ECG for safety assessment will be obtained as outlined in the 
Schedule of Activities (see Section 1.3) using an ECG machine that automatically 


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calculates the heart rate (HR) and measures PR, QRS, QT, and QTc intervals. 
Refer to Section 7.1.2 for QTc withdrawal criteria and any additional QTc 
readings that may be necessary. At each time point at which triplicate ECGs are 
required, 3 individual ECG tracings should be obtained as closely as possible in 
succession, but no more than 2 minutes apart. The full set of triplicates should be 
completed in less than 4 minutes. 
 High-precision 12-lead ECG tracings for cardiodynamic ECG evaluation will be 
extracted from the Holter recording as outlined in the Schedule of Activities (see 
Section 1.3) and analyzed according to the procedures and algorithm of the ECG 
vendor Core Laboratory. Electrocardiograms will be recorded after vital signs and 
prior to blood draws. Study participants will rest for 10 minutes in a supine 
position before and during the vital signs, ECG recording, and blood draws and 
the rest must be documented in source notes. The Holter equipment will be 
supplied and supported by ERT. All ECG data will be collected using a Global 
Instrumentation (Manlius, NY, USA) M12R ECG continuous 12-lead digital 
recorder. The continuous 12-lead digital ECG data will be stored on secure digital 
memory cards. 
The following will be applied in ERT’s core laboratory: 
 ECG analysts are blinded to the study participant, visit and study intervention 
allocation. 
 Baseline and on-treatment ECGs for a particular study participant will be over-
read on the same lead and will be analyzed by the same reader. 
 The primary analysis lead is Lead II. If Lead II is not analyzable, then primary 
lead of analysis will be changed to another lead for the entire study participant 
data set. 
The following is a brief description of ECG analysis methods utilized by ERT’s core 
laboratory. 
8.2.3.1 
TQT Plus Electrocardiogram Extraction Technique 
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the “TQT Plus method”, a computer-assisted and statistical process 
utilized by ERT. The method enables extraction of ECGs with the lowest HR variability 
and noise within the protocol-specified extraction time window (eg, the HR and QT 
changes from beat-to-beat in the range of < 10%). At each protocol-specified time point, 
10 ECG replicates will be extracted from a 5-minute “ECG window” (typically, the last 
5 minutes of the 15-minute period when the study participant is maintained in a supine 
position). 
8.2.3.2 
Expert-Precision QT Analysis 
Expert-precision QT analysis will be performed on all analyzable (nonartifact) beats in 
the 10 ECG replicates. Statistical quality control (QC) procedures are used to review and 


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assess all beats and identify “high” and “low” confidence beats using several criteria, 
including: 
● QT or QTc values exceeding or below certain thresholds (biologically unlikely) 
● RR values exceeding or below certain thresholds (biologically unlikely) 
● Rapid changes in QT, QTc, or RR from beat to beat 
Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” are performed using COMPAS software. 
All low confidence beats are reviewed manually and adjudicated using pass-fail criteria. 
The final QC assessment is performed by a cardiac safety specialist. The beats found 
acceptable by manual review are included in the analysis. The median QT, QTc, and RR 
value from each extracted replicate is calculated, and then the mean of all available 
medians from a nominal time point is used as the study participant’s reportable value at 
that time point. 
Categorical T-wave morphology analysis and the measurement of PR and QRS intervals 
will be performed manually in 3 of the 10 ECG replicates at each time point. Each 
fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) 
is electronically marked. 
For T-wave morphology and U-wave presence, treatment-emergent changes will be 
assessed, ie, changes not present at baseline. For each category of T-wave morphology 
and of U-waves, the category will be deemed as present if observed in all replicates at the 
time point. For baseline, the category will be deemed as present if observed in any 
replicates from all time points that constitute baseline. The T-wave morphology 
categories are described as follows. 
Table 8-1 
T-wave Morphology and U-wave Presence Categories 
(Assessed Manually) 
Category 
Description 
Normal T-wave 
Any positive T-wave not meeting any criterion below 
Flat T-wave 
T amplitude < 1 mm (either positive or negative) including flat 
isoelectric line 
Notched T-wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on ascending or 
descending arm of the positive T-wave 
Biphasic 
T-wave that contains a second component with an opposite phase that is 
at least 0.1 mV deep (both positive/negative and negative/positive and 
polyphasic T-waves included) 
Normal T-wave (-) 
T amplitude that is negative, without biphasic T-wave or notches 
Notched T-wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on descending or 
ascending arm of the negative T-wave 
U-waves 
Presence of abnormal U-waves 
 


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8.2.4 
Clinical Safety Laboratory Assessments 
 See Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be 
performed and the Schedule of Activities (Part 1 in Figure 1-2, Part 2 in  
Figure 1-3, and Part 3 in Figure 1-4 and Figure 1-5) for the timing and frequency.  
 The investigator must review the laboratory test results, document this review, 
and record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed 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 the 
sponsor notified. 
o All protocol-required laboratory assessments, as defined in Section 10.2 
(Appendix 2), must be conducted in accordance with the applicable local 
laboratory SOPs and the Schedule of Activities (Part 1 in Figure 1-2, Part 2 in 
Figure 1-3, and Part 3 in Figure 1-4 and Figure 1-5). 
o If laboratory values from nonprotocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, an 
SAE or AE or dose modification), then the results must be recorded in the 
eCRF.  
8.2.5 
Ophthalmological Examinations 
 Ophthalmological examinations will include fundoscopy, tonometry (intraocular 
pressure), and a visual acuity test. Assessments will be carried out by an 
ophthalmologist at the specified time points in the Schedule of Activities (Part 1 
in Figure 1-2, Part 2 in Figure 1-3, and Part 3 in Figure 1-4 and Figure 1-5).  
 The investigator must review the ophthalmological results, document this review, 
and record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. Clinically significant abnormal findings would include new 
conditions detected or diagnosed after study intervention administration even 
though they may have been present before the start of the study (see Section 10.3 
[Appendix 3]). The examinations must be filed with the source documents. 
 All ophthalmological results 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. 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 the sponsor notified. 


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8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.3 (Appendix 3). The 
assessment of intensity (including HIV grading system), assessment of causality, and 
procedures for recording, evaluating, follow-up and reporting of AEs are also 
summarized in Section 10.3 (Appendix 3). 
Adverse events reported by the study participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative) must be captured in 
source documents. 
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 intervention and/or 
study procedures, or that caused the participant to discontinue the study intervention (see 
Section 7). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information  
All AEs/SAEs will be collected from the date of signing of the ICF to up to 10 days after 
the last dose of study intervention or last Follow-up visit.  
All SAEs will be recorded in the eCRF and reported to the sponsor or designee within 
24 hours, as indicated in Section 10.3 (Appendix 3). The investigator or qualified 
designee will submit any updated SAE information to the sponsor within 24 hours of 
awareness.  
Investigators or qualified designees are not obligated to actively seek AEs or SAEs after 
conclusion of the study participation. However, if the investigator or qualified designee 
learns of any SAE, including a death, at any time after a participant is no longer in the 
study, and the investigator or qualified designee considers the event to be reasonably 
related to the study treatment or study participation, the investigator or qualified designee 
must promptly notify the sponsor via phone, e-mail, or fax (see Section 10.3 
[Appendix 3]). Investigator assessment of causality must be included with all SAEs 
reported to the sponsor. Serious adverse events with missing investigator causality will be 
followed up by the CRO urgently until response is provided to the sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3 
(Appendix 3). 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
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.  


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8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator or qualified designee is required to 
proactively follow each participant at subsequent visits/contacts. All AEs/SAEs and non-
serious AEs of special interest (as defined in Section 8.3.6), will be followed until 
resolution, stabilization, 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 
given in Section 10.3 (Appendix 3). 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
● Prompt notification by the investigator (or qualified designee) to the sponsor of a 
SAE is essential so that legal obligations and ethical responsibilities towards the 
safety of participants and the safety of a study intervention under clinical 
investigation are met.  
● The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs), and investigators. 
● Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSARs) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
● An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (eg, summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate, according to local requirements. 
8.3.5 
Pregnancy 
● Details of all pregnancies in female participants and, if indicated, female partners 
of male participants will be collected after the start of study intervention and until 
3 months after the last dose. 
● If a female study participant becomes pregnant during the study, the investigator 
(or subinvestigator) will immediately discontinue study intervention. 
● If a pregnancy is reported, the investigator should inform the sponsor within 
24 hours of learning of the pregnancy and should follow the procedures, which 
require utilization of the Pregnancy Form, as outlined in Section 10.4 
(Appendix 4). 
● Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs. 
● The outcome of the pregnancy (ie, birth, miscarriage, abortion) should be 
followed by the investigator and must also be reported using the Pregnancy Form. 


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8.3.6 
Adverse Events of Special Interest 
Adverse events of special interest include GI AEs such as nausea, vomiting, diarrhea, etc. 
If a GI AE occurs, the electronic data capture (EDC) system will generate an additional 
case report form to collect further information regarding the event. 
8.4 
Special Situations – Abuse, Misuse, Overdose, and Medication 
Error 
Abuse, misuse, overdose, or medication error of the study intervention (Special 
Situations, as defined below) must be reported to the sponsor (sponsor's medical monitor) 
via EDC using a Special Situations Report Form as soon as possible. If there are 
associated SAEs, the investigator (or qualified designee) must also complete and submit 
an SAE submission in EDC as well. 
● Abuse - persistent or sporadic, intentional excessive use of a study intervention(s), 
which is accompanied by harmful physical or psychological effects. 
● Misuse - intentional and inappropriate use of a study intervention(s) other than as 
directed or indicated at any dose. 
● Overdose - intentional or unintentional intake of study intervention(s) in excess of 
the assigned dose in the protocol.  
● Medication Error - any unintended error in the prescribing, dispensing or 
administration of a study intervention(s) (including intercepted error). Cases of 
study participants missing doses of study intervention(s) are not considered 
reportable as medication error. 
8.4.1 
Treatment of Overdose 
For this study, any dose of study intervention greater than that required by the phase of 
the protocol will be considered an overdose and reported as a special situation. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities 
until all AEs or abnormalities have resolved or are stable. 
3. Obtain a plasma sample for PK analysis daily from the date of the last dose of 
study intervention 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 
in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant. 






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9. STATISTICAL CONSIDERATIONS  
9.1 
Statistical Hypotheses 
This is a Phase 1 dose-finding and food-effect study of the safety, tolerability, ventricular 
repolarization, PK of midazolam with and without S-648414, PK of dolutegravir with and 
without S-648414, and PK of S-648414 with and without dolutegravir; therefore, there is 
no formal statistical hypothesis in this study. 
9.2 
Sample Size Determination  
Up to 50 healthy adult study participants in Part 1, 20 healthy adult study participants in 
Part 2, and 28 healthy adult study participants in Part 3 will be enrolled. 
No formal calculations were performed to determine sample size for this study. 
9.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled  
All participants who sign the ICF. 
Randomly Assigned to 
Study Intervention 
All participants randomly assigned to study intervention. 
Safety 
All participants randomly assigned to study intervention and who take 
at least 1 dose of study intervention. Participants will be analyzed 
according to the intervention they actually received. 
PK 
The PK concentration population includes all study participants who 
receive at least 1 dose of S-648414 or dolutegravir and have at least 1 
evaluable concentration in plasma or urine. This population will be 
used for the concentration listing. 
The PK parameter population includes all study participants with at 
least 1 PK parameter estimated appropriately. This population will be 
used for PK parameter listing and summary. This population will also 
be used for plotting of the concentration-time data, the concentration 
summary and statistical analysis. 
QT/QTc 
All study participants in the Safety population who have 
measurements at baseline as well as on-treatment, with at least 1 
postdose time point with a valid ΔQTcF value. This analysis 
population will be used for the by-time point and categorical analyses 
for the cardiodynamic ECG parameters.  
PK/QTc 
All study participants who are in both the QT/QTc and PK populations 
with at least 1 pair of postdose plasma concentration and QTcF data 
from the same time point as well as study participants in the QT/QTc 
population who received placebo. This analysis population will be 
used for the concentration-QTc analysis.  
ECG = electrocardiogram; ICF = informed consent form; PK = pharmacokinetic; QTcF = Fridericia’s 
corrected QT; Δ = change from baseline 
 


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9.4 
Statistical Analyses 
The SAP will be finalized before unblinding/database lock. The SAP will describe the 
study participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the 
planned statistical analyses of the primary and secondary endpoints.  
Unless otherwise noted, continuous variables will be summarized by using the number of 
nonmissing observations, arithmetic mean, standard deviation, median, minimum, and 
maximum values as descriptive statistics; categorical variables will be summarized by 
using the frequency count and the percentage of study participants in each category as 
descriptive statistics. All safety and demographic analyses described in the sections 
below will be performed for each part of the study. 
All analyses and tabulations will be performed by using both SAS Version 9.2 or higher 
and WinNonlin Version 6.2.1 or higher. 
9.4.1 
Disposition 
Among the study participants enrolled into the study, the number and percentage who 
complete the study and who prematurely discontinued the study will be summarized. In 
addition, reasons leading to study discontinuation will be summarized. The number of 
study participants included in each analysis population will also be presented. 
9.4.2 
Demographics, Treatment Compliance, and Prior and 
Concomitant Therapies 
Demographic and baseline characteristics will be summarized with descriptive statistics 
for the safety population. 
The study intervention exposure and compliance will be listed. 
Prior therapies for drugs will be coded using the World Health Organization (WHO) 
Drug Dictionary. Study participants who have received prior therapy(ies) will be listed 
for the safety population. 
Concomitant therapies for drugs will be coded using the WHO Drug Dictionary. Study 
participants who received concomitant therapy(ies) will be listed for the safety 
population. 


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9.4.3 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Endpoint 
Statistical Analysis Methods 
Adverse event 
The number of study participants who experience at least 1 AE, death, other 
SAEs and AEs leading to study intervention (S-648414, midazolam, 
dolutegravir. or placebo) withdrawal will be counted for each treatment group. 
The number of AEs will also be presented. Treatment-related AEs will be 
summarized in the same manner as the overall summary of AEs. 
The number of study participants who experience at least 1 AE and incidence 
by system organ class and preferred term will be presented for each treatment 
group. The summary of AEs by severity will also be presented by system 
organ class and preferred term. 
Cardiodynamic ECG 
evaluation  
Summary statistics for each parameter and for the change from baseline to 
each time point will be calculated. 
Clinical laboratory 
tests, vital signs, and 
ECGs 
Summary statistics for each parameter and for the change from baseline to 
each time point will be calculated. 
Physical 
examinations 
Will be summarized by visit. 
AE = adverse event; ECG = electrocardiogram; SAE = serious adverse event 
 
9.4.4 
Other Analyses  
9.4.4.1 
Pharmacokinetic Analyses 
All PK analyses will be performed on the PK Population.  
Endpoint 
Statistical Analysis Methods 
Primary 
 
To evaluate the effect of S-648414 on the pharmacokinetics of dolutegravir 
(Section 9.4.4.1.8) 
 
To evaluate the effect of dolutegravir on the pharmacokinetics of S-648414 
(Section 9.4.4.1.9) 
Secondary 
 
Pharmacokinetic parameters (See Section 9.4.4.1.2 for statistical analyses). 
 
Effect of high-fat meal (See Section 9.4.4.1.5 for statistical analyses). 
 
Inhibition or induction of the CYP3A enzymes (See Section 9.4.4.1.7 for 
statistical analyses). 
 
9.4.4.1.1 
Plasma and Urine Concentration 
Plasma concentrations of S-648414, midazolam, and dolutegravir will be listed and 
summarized by dosing regimen and nominal sampling time with the number of 
nonmissing observations (N), arithmetic mean (mean), standard deviation (SD) and 
coefficient of variation (CV%, calculated by SD/mean × 100), geometric mean and 
coefficient of variation for geometric mean (Geometric CV%), and median, minimum, 
and maximum values at each sampling time. The Geometric CV% will be calculated 
according to a formula Geometric CV% = [exp (sd2)-1]1/2 × 100, where SD is the 
standard deviation for natural log (ln)-transformed data. Time course profiles for plasma 


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concentrations will be presented by appropriate graphics. In Part 2, achievement of steady 
state for plasma S-648414 concentration and in Part 3 achievement of steady state for 
plasma S-648414 and dolutegravir will be assessed by visual inspection of trough 
concentration data. 
For summary of plasma concentration, plasma concentration below the lower limit of 
quantification (BLQ) will be treated as zero (0) for calculations of mean, SD, CV%, 
median, minimum, and maximum values and treated as missing for calculation of 
geometric mean and Geometric CV% mean values.  
Urine volume and urine concentration data for S-648414 will be listed. In Part 1, time 
course profiles for cumulative fraction of dose excreted in urine will be presented by 
appropriate graphics. 
9.4.4.1.2 
Pharmacokinetic Parameters 
The following PK parameters will be calculated, whenever possible, for S-648414, 
midazolam, and dolutegravir from plasma and urine concentration data by 
noncompartmental methods. Other parameters may be computed, as appropriate, upon 
review of the data. The estimated PK parameters will be computed for each study 
participant using the actual sample collection times recorded during the study. 
Pharmacokinetic parameters (S-648414) for Part 1: 
Cmax (ng/mL) 
Maximum plasma concentration 
Tmax (hr) 
Time to maximum plasma concentration 
AUC0-last (ng·hr/mL) Area under the concentration-time curve from time zero to the 
time of the last quantifiable concentration after dosing, 
calculated by linear trapezoidal method when concentrations are 
increasing and by logarithmic trapezoidal method when 
concentrations are decreasing (Linear Up/Log Down 
Trapezoidal Method) 
AUC0-inf (ng·hr/mL) 
Area under the concentration-time curve extrapolated from time 
zero to infinity defined as AUC0-last + (Clast/λz), where Clast is the 
last measurable plasma concentration and λz is the plasma 
terminal elimination rate constant 
t1/2,z (hr) 
Terminal elimination half-life, where t1/2,z = (ln2)/λz 
λz (hr-1) 
Terminal elimination rate constant, where λz is the magnitude of 
the slope of the linear regression of the log concentration versus 
time profile during the terminal phase 
MRT (hr)  
Mean residence time, where MRT = AUMC0-inf/AUC0-inf and 
AUMC0-inf is the area under the first moment curve extrapolated 
to infinity 
CL/F (L/hr) 
Apparent total clearance estimated according to: CL/F = 
Dose/AUC0-inf for treatment groups 


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Vz/F (L) 
Apparent volume of distribution in the terminal elimination 
phase, estimated according to: Vz /F = Dose/AUC0-inf/λz 
Feu0-96 (%) 
Fraction of dose excreted in urine from 0 to 96 hours; calculated 
as Aeu0-96/Dose × 100 and Aeu0-96 is cumulative amount of the 
drug excreted in urine during a given collection time interval 
from 0 to 96 hours 
CLR (L/hr) 
Renal clearance estimated according to: CLR = Aeu0-96/AUC0-last 
 
Pharmacokinetic parameters (S-648414) for Part 2: 
Cmax (ng/mL) 
Maximum plasma concentration on Day 1 and Day 14 
Tmax (hr) 
Time to maximum plasma concentration on Day 1 and Day 14 
AUC0-τ (ng·hr/mL) 
Area under the concentration-time curve over the dosing 
interval τ (24 hours) on Day 1 and Day 14, calculated by Linear 
Up/Log Down Trapezoidal Method 
t1/2,z (hr) 
Terminal elimination half-life, where t1/2,z = (ln2)/λz on Day 14 
λz (hr-1) 
Terminal elimination rate constant, where λz is the magnitude of 
the slope of the linear regression of the log concentration versus 
time profile during the terminal phase on Day 14 
CL/F (L/hr) 
Apparent total clearance estimated according to: CL/F = 
Dose/AUC0-τ on Day 14 
Vz/F (L) 
Apparent volume of distribution in the terminal elimination 
phase on Day 14, estimated according to: Vz /F = Dose/AUC0-
τ/λz 
Feu0-τ (%) 
Fraction of dose excreted in urine over the dosing interval τ 
(24 hours) on Day 14; calculated as Aeu0-τ / Dose × 100, where 
Aeu0-τ is the amount of drug excreted in urine 
CLR (L/hr) 
Renal clearance on Day 14, calculated as CLR = Aeu0-τ / AUC0-τ 
and Aeu0-τ is cumulative amount of the drug excreted in urine 
during a given collection time over the dosing interval τ 
(24 hours) 
 
Pharmacokinetic parameters for midazolam on Day -2 and Day 14: 
Cmax (ng/mL) 
Maximum plasma concentration 
Tmax (hr) 
Time to maximum plasma concentration 
AUC0-last (ng·hr/mL) Area under the concentration-time curve from time zero to the 
time of the last quantifiable concentration after dosing, 
calculated by the Linear Up/Log Down Trapezoidal Method 
AUC0-inf (ng·hr/mL) 
Area under the concentration-time curve extrapolated from time 
zero to infinity defined as AUC0-last + (Clast/λz), where Clast is the 
last measurable plasma concentration and λz is the plasma 
terminal elimination rate constant 


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t1/2,z (hr) 
Terminal elimination half-life, where t1/2,z = (ln2)/λz 
λz (hr-1) 
Terminal elimination rate constant, where λz is the magnitude of 
the slope of the linear regression of the log concentration versus 
time profile during the terminal phase 
MRT (hr)  
Mean residence time, where MRT = AUMC0-inf/AUC0-inf and 
AUMC0-inf is the area under the first moment curve extrapolated 
to infinity 
 
Pharmacokinetic parameters (S-648414) for Part 3: 
Cmax (ng/mL) 
Maximum plasma concentration on Day 21 and Day 28 
Tmax (hr) 
Time to maximum plasma concentration on Day 21 and Day 28 
Cτ (ng/mL) 
Plasma concentration at the end of the dosing interval τ 
(24 hours) on Day 21 and Day 28 
AUC0-τ (ng·hr/mL) 
Area under the concentration-time curve over the dosing 
interval τ (24 hours) on Day 21 and Day 28, calculated by 
Linear Up/Log Down Trapezoidal Method 
CL/F (L/hr) 
Apparent total clearance estimated according to: 
CL/F =Dose/AUC0-τ on Day 21 and Day 28 
 
Pharmacokinetic parameters (dolutegravir) for Part 3: 
Cmax (ng/mL) 
Maximum plasma concentration on Day 7 and Day 28 
Tmax (hr) 
Time to maximum plasma concentration on Day 7 and Day 28 
Cτ (ng/mL) 
Plasma concentration at the end of the dosing interval τ 
(24 hours) on Day 7 and Day 28 
AUC0-τ (ng·hr/mL) 
Area under the concentration-time curve over the dosing 
interval τ (24 hours) on Day 7 and Day 28, calculated by Linear 
Up/Log Down Trapezoidal Method 
CL/F (L/hr) 
Apparent total clearance estimated according to: 
CL/F = Dose/AUC0-τ on Day 7 and Day 28 
The estimated PK parameters will be summarized by dosing regimen with N, mean, SD, 
CV%, geometric mean, Geometric CV%, median, minimum, and maximum values. The 
Tmax will be summarized by analyte and dosing regimen with N, mean, SD, CV%, 
median, minimum, and maximum values. If the number of PK parameter data is < 3, the 
data will not be summarized. 
If the number of data points used to calculate λz is < 3 or the calculated coefficient of 
determination (R2) value for λz is < 0.800, then that study participant’s λz, and AUC0-inf, 
t1/2,z, MRT, CL/F, and Vz/F derived from λz will be flagged in the data listing, and 
excluded from the descriptive and statistical analysis. If λz cannot be determined, then 
AUC0-inf, t1/2,z, MRT, CL/F, and Vz/F will not be estimated. 


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In addition to the parameters listed above, the extrapolated percent of AUC0-inf, calculated 
as AUCextr (%) = 100 × (AUC0-inf − AUC0-last)/AUC0-inf, will be determined. If the 
AUCextr is greater than 20%, then AUC0-inf, MRT, CL/F, and Vz/F derived from AUC0-inf 
will be flagged in the data listing and excluded from the descriptive statistics and 
statistical analysis. 
Individual plasma concentrations, if deemed to be anomalous, may be excluded from the 
analysis at the discretion of the PK study director. Any such exclusion will be clearly 
represented in the study report along with justification for exclusion. 
For the calculations of PK parameters, BLQ before the occurrence of the first quantifiable 
concentration will be treated as zero, and BLQ after the first occurrence of the 
quantifiable concentration will be treated as missing. Urine BLQ concentrations will be 
treated as 0 for calculation of Aeu0-96 and Aeu0-τ. 
Pharmacokinetic calculations will be performed by using WinNonlin Version 6.2.1 or 
higher. 
9.4.4.1.3 
Dose Proportionality 
Dose proportionality of PK parameter of S-648414 will be examined in Part 1 except for 
Step 3-2 (Tablet Fed), and in Part 2. In Part 1, dose proportionality will be assessed for 
Cmax, AUC0-last, and AUC0-inf of S-648414 using the power model. The power model 
assumes a linear relationship between the ln-transformed parameter and ln-transformed 
dose. 
 
ln (Parameter) = α + β × ln (Dose) + Random error 
Where Parameter is a given PK parameter, α is the intercept, β is the slope, and Random 
error is a random residual error. Dose proportionality implies that slope = 1 and will be 
assessed by estimating mean slope with the corresponding confidence interval (95% CI) 
using SAS Proc Reg from the power model. 
In the case where the 95% CI of the slope from the power model does not include 1, the 
differences in ln-transformed Cmax, AUC0-last, and AUC0-inf of S-648414 will be examined 
between treatment groups. An analysis of variance (ANOVA) will be performed using 
SAS Proc Mixed. An ANOVA will be also performed for Part 2. The point estimates and 
90% CIs will be generated for the ratios of all treatment group combinations for ln-
transformed Cmax and AUC (AUC0-last and AUC0-inf for Part 1 and AUC0-τ for Part 2). The 
point estimates and 90% CIs will be back-transformed to obtain the corresponding 
geometric least squares mean ratios and 90% CIs. The following linear model will be 
used: 
 
ln (Parameter) = Treatment group + Random error 
Where Parameter is a given PK parameter, Treatment group is a fixed treatment group 
effect and Random error is a random residual error.  


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The relationship of Cmax, AUC0-last, and AUC0-inf to dose will be graphically represented. 
Dose proportionality will be concluded based on the point estimates and CIs of the power 
model or the ANOVA model and visual inspection of the corresponding plots. 
9.4.4.1.4 
Dose Independency 
Dose independence of PK parameters of S-648414 will be examined between the 
treatment groups in Part 1 except for Step 3-2 (Tablet Fed), and Part 2. For t1/2,z, CL/F, 
Vz/F, MRT, and CLR, the difference between treatment groups will be examined for dose 
independence using the ANOVA model. An ANOVA will be performed using SAS Proc 
Mixed. The point estimates and 90% CIs will be generated for all treatment group 
combinations for ln-transformed t1/2,z, CL/F, Vz/F, MRT, and CLR. The point estimates 
and 90% CIs will be back-transformed to obtain the corresponding geometric least 
squares mean ratios and 90% CIs. The following linear model will be used: 
ln (Parameter) = Treatment group + Random error 
Where Parameter is a given PK parameter, Treatment group is a fixed treatment group 
effect and Random error is a random residual error.  
The relationship of t1/2,z, CL/F, Vz/F, MRT, and CLR to dose will be graphically 
represented. 
Dose independency will be concluded based on the point estimates and 90% CIs of the 
ANOVA model and visual inspection of the corresponding plots. 
9.4.4.1.5 
Effect of Food 
When data are available, the PK after administration of S-648414 tablet will be compared 
between the fasted state (Step 3-1) and the fed state (Step 3-2). An ANOVA will be 
performed using SAS Proc Mixed for ln-transformed Cmax, AUC0-last, AUC0-inf, and t1/2,z. 
In case of unbalanced data, the Kenward-Roger method will be used to compute the 
denominator degrees of freedom for the tests of fixed effects in this analysis. The point 
estimates and 90% CIs will be generated for the differences between PK in the fed state 
and PK in the fasted state for ln-transformed Cmax, AUC0-last, AUC0-inf, and t1/2,z. The 
point estimates and 90% CIs will be back-transformed to obtain the corresponding 
geometric least squares mean ratios and 90% CIs as the following ratio. 
(PK in the fed state [Step 3-2]) / (PK in the fasted state [Step 3-1]) 
The following linear mixed effects model will be used: 
 
ln (Parameter) = Food condition + Subject + Random error 
Where Food condition is a fixed effect of food condition, Subject is a random effect of 
study participant, and Random error is a random residual error.  


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The comparison of Cmax, Tmax, AUC0-last, AUC0-inf, and t1/2,z between the fasted state and 
the fed state will be graphically represented. 
The effect of food will be concluded based on the point estimates and 90% CIs of the 
ANOVA model and visual inspection of the corresponding plots. 
9.4.4.1.6 
Accumulation Ratio 
When data are available, the accumulation ratios of S-648414 calculated as ratios of 
Day 14 to Day 1 will be assessed in Part 2. An ANOVA will be performed using SAS 
Proc Mixed for ln-transformed Cmax and AUC0-τ. In case of unbalanced data, the 
Kenward-Roger method will be used to compute the denominator degrees of freedom for 
the tests of a fixed effect in the analysis. The point estimates and their 90% CIs will be 
generated for the differences between Days 1 and 14 for ln-transformed Cmax and AUC0-τ 
in each dose group. The point estimates and the 90% CIs will be back-transformed to 
obtain the corresponding geometric least squares mean ratios and the 90% CIs. The 
following linear mixed effects model will be used: 
ln (Parameter) = Day + Subject + Random error 
Where Day is a fixed effect of day, Subject is a random effect of study participant, and 
Random error is a random residual error. 
9.4.4.1.7 
Effect of S-648414 on the Pharmacokinetics of Midazolam 
When data are available, the effect of S-648414 on the PK of midazolam will be 
assessed. An ANOVA will be performed using SAS Proc Mixed for ln-transformed Cmax, 
AUC0-last, and AUC0-inf of midazolam. In case of unbalanced data, the Kenward-Roger 
method will be used to compute the denominator degrees of freedom for the tests of a 
fixed effect in the analysis. The point estimates and their 90% CIs will be generated for 
the differences between midazolam coadministered with S-648414 and midazolam alone 
for ln-transformed Cmax, AUC0-last, and AUC0-inf. The point estimates and their 90% CIs 
will be back-transformed to obtain the corresponding geometric least squares mean ratios 
and 90% CIs as the following ratio: 
(midazolam coadministered with S-648414) / (midazolam alone) 
The following linear mixed effects model will be used: 
ln (Parameter) = Treatment + Subject + Random error 
Where Treatment is a fixed effect of treatment, Subject is a random effect of study 
participant, and Random error is a random residual error.  
The drug interaction will be assessed by whether the 90% CIs for Cmax, AUC0-last, and 
AUC0-inf of midazolam are completely contained within the range of 0.8000 to 1.2500. 


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The comparison of Cmax, AUC0-last, and AUC0-inf between midazolam alone and 
midazolam coadministered with S-648414 will be graphically represented. 
The effect of S-648414 on the PK of midazolam will be concluded based on the point 
estimates and 90% CIs of the ANOVA model and visual inspection of the corresponding 
plots. 
9.4.4.1.8 
Effect of S-648414 on the Pharmacokinetics of Dolutegravir 
When data are available, the effect of S-648414 on the PK of dolutegravir will be 
assessed. An ANOVA will be performed using SAS Proc Mixed for ln-transformed Cmax, 
Cτ, and AUC0-τ of dolutegravir. In case of unbalanced data, the Kenward-Roger method 
will be used to compute the denominator degrees of freedom for the tests of a fixed effect 
in the analysis. The point estimates and their 90% CIs will be generated for the 
differences between dolutegravir coadministered with S-648414 and dolutegravir alone 
for ln-transformed Cmax, Cτ, and AUC0-τ. The point estimates and their 90% CIs will be 
back-transformed to obtain the corresponding geometric least squares mean ratios and 
90% CIs as the following ratio: 
(dolutegravir coadministered with S-648414) / (dolutegravir alone) 
The following linear mixed effects model will be used: 
ln (Parameter) = Treatment + Subject + Random error 
Where Treatment is a fixed effect of treatment, Subject is a random effect of study 
participant, and Random error is a random residual error.  
The drug interaction will be assessed by whether the 90% CIs for Cmax, Cτ, and AUC0-τ of 
dolutegravir are completely contained within the range of 0.8000 to 1.2500. 
The comparison of Cmax, Cτ, and AUC0-τ between dolutegravir alone and dolutegravir 
coadministered with S-648414 will be graphically represented. 
The effect of S-648414 on the PK of dolutegravir will be concluded based on the point 
estimates and 90% CIs of the ANOVA model and visual inspection of the corresponding 
plots. 
9.4.4.1.9 
Effect of Dolutegravir on the Pharmacokinetics of S-648414 
When data are available, the effect of dolutegravir on the PK of S-648414 will be 
assessed. An ANOVA will be performed using SAS Proc Mixed for ln-transformed Cmax, 
Cτ, and AUC0-τ of S-648414. In case of unbalanced data, the Kenward-Roger method will 
be used to compute the denominator degrees of freedom for the tests of a fixed effect in 
the analysis. The point estimates and their 90% CIs will be generated for the differences 
between S-648414 coadministered with dolutegravir and S-648414 alone for ln-
transformed Cmax, Cτ, and AUC0-τ. The point estimates and their 90% CIs will be back-


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transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs 
as the following ratio:  
(S-648414 coadministered with dolutegravir) / (S-648414 alone) 
The following linear mixed effects model will be used: 
ln (Parameter) = Treatment + Subject + Random error 
Where Treatment is a fixed effect of treatment, Subject is a random effect of study 
participant, and Random error is a random residual error.  
The drug interaction will be assessed by whether the 90% CIs for Cmax, Cτ, and AUC0-τ of 
S-648414 are completely contained within the range of 0.8000 to 1.2500. 
The comparison of Cmax, Cτ, and AUC0-τ between S-648414 alone and S-648414 
coadministered with dolutegravir will be graphically represented. 
The effect of dolutegravir on the PK of S-648414 will be concluded based on the point 
estimates and 90% CIs of the ANOVA model and visual inspection of the corresponding 
plots. 
9.4.4.2 
Cardiodynamic Electrocardiogram Evaluation 
When data are available, the relationship between S-648414 plasma concentrations and 
QT interval will be analyzed to evaluate the effect of S-648414 on the QTc interval using 
the Fridericia’s method (QTcF). Details of the cardiodynamic ECG evaluation will be 
provided in the SAP. The results of cardiodynamic ECG evaluation will be reported as a 
separate report. 
The primary analysis will be based on concentration-QTc modeling of the relationship 
between the concentrations of S-648414 and change-from-baseline QTcF (∆QTcF) with 
the intent to exclude an effect > 10 msec at clinically relevant S-648414 plasma 
concentrations. In addition, the effect of S-648414 on the placebo-corrected ∆QTcF, 
ΔHR, ΔPR, and ΔQRS (∆∆QTcF, ΔΔHR, ΔΔPR, and ΔΔQRS) will be evaluated at each 
postdosing time point (“by-time point” analysis) using the Intersection Union Test. An 
analysis of categorical outliers will be performed for changes in HR, PR, QRS, QTcF, 
T-wave morphology and U-wave presence.  
9.5 
Interim Analyses 
No interim analyses for efficacy are planned in this study. However, ongoing assessments 
of the safety, tolerability, and PK will occur between the investigator and the sponsor. 
Criteria for determining whether to proceed to next dose group are included in 
Section 6.6.1 (Part 1) and Section 6.6.2 (Part 2). To assist with the evaluation and dose 
selection for the S-648414 Proof of Concept study, the sponsor will be unblinded after 
the completion of Part 2 and an evaluation of safety and PK data from Parts 1 and 2 will 
be conducted. 


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No independent data monitoring committee will be established for this study. 
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: 
 Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator’s Brochure, 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 the study is 
initiated. Competent authority notification, review, and approval may be required 
as appropriate according to local country requirements. 
 Any amendments to the protocol will require competent authority and/or IRB/IEC 
approval (as appropriate) before implementation of changes made to the study 
design, except for changes necessary to eliminate an immediate hazard to study 
participants.  
 For studies to be submitted as part of a European Marketing Authorization 
Application, the sponsor will select a Clinical Study Report Coordinating 
investigator who will sign the Clinical Study Report. 
 The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2 
Financial Disclosure 
The information on financial disclosure for investigators will be addressed in a separate 
agreement between the sponsor and the investigator. 


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10.1.3 
Informed Consent Process 
 The investigator or his/her representative must explain the nature of the study to 
the study participant or his/her legally authorized representative and answer all 
questions regarding the study.  
 Study participants must be informed that their participation is voluntary. Study 
participants will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, and Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
 The medical record must include a statement that written informed consent was 
obtained before the study participant was enrolled in the study and the date that 
written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
 Study participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
 A copy of the signed ICF(s) must be provided to the study participant or the study 
participant’s legally authorized representative.  
A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within 28 days from the previous ICF signature date. 
A separate ICF will address the use of remaining mandatory samples for optional 
exploratory research. The investigator or authorized designee will explain to each study 
participant the objectives of the exploratory research. Study participants will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a 
participant’s agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide 
this separate signature. 
10.1.4 
Data Protection 
● Study participants will be assigned a unique identifier by the sponsor. Any study 
participant records or datasets that are transferred to the sponsor will contain the 
identifier only; study participant names or any information that would make the 
study participant directly identifiable will not be transferred.  
● The study participant must be informed that his/her personal study-related data 
will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant.  
● The study participant must be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. 


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10.1.5 
Dissemination of Clinical Study Data 
All information regarding S-648414 supplied by the sponsor to the investigator is 
privileged and confidential information. The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the 
sponsor. It is understood that there is an obligation to provide the sponsor with complete 
data obtained during the study. The information obtained from the clinical trial will be 
used toward the development of S-648414 and may be disclosed to regulatory 
authority(ies), other investigators, corporate partners, or consultants as required. 
The sponsor will retain ownership of all data. All proposed publications based on the 
study will be subject to the sponsor's approval requirements. 
10.1.6 
Data Quality Assurance 
 All study participant data relating to the study will be recorded on an eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data and 
central ECG data). The investigator is responsible for verifying that data entries 
are accurate and correct by electronically signing the eCRF.  
 The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF.  
 The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and sponsor and/or regulatory agency inspections and provide direct access to 
source data documents.  
 The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data.  
 Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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.  
 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion, 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  
10.1.7 
Source Documents 
Source documents provide evidence of the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
Data 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 


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need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
Source documents are defined as original documents, data, and records (eg, hospital 
records, clinical and office charts, laboratory notes, memoranda, study participant's 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, 
x-rays, study participant files, and records kept at the pharmacy, laboratories, and 
medico-technical departments involved in the clinical trial). 
10.1.8 
Study and Site Closure 
The sponsor/designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of the sponsor.  
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected, data have been collected, 
a study-site closure visit has been performed, and notification to the IRB/IEC has been 
made.  
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
 Inadequate recruitment of participants by the investigator 
 Discontinuation of further study intervention development 
10.2 Appendix 2: Clinical Laboratory Tests 
 The tests detailed in Table 10-1 will be performed by the local laboratory. 
 Protocol-specific requirements for inclusion or exclusion of study participants are 
detailed in Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 














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Contraception Guidance: 
Male study participants 
Male study participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following during the treatment period and for at 
least 3 months after the last dose of study intervention:  
 Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
 Agree to use a male condom plus partner use of a contraceptive method with a 
failure rate of < 1% per year as described in Table 10-2 when having penile-
vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant 
In addition, male participants must refrain from donating sperm for the duration of the 
study and for 3 months after the last dose of study intervention. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment period. 
Table 10-2 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of < 1% per year when used consistently and correctly.  
 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
 
Oral  
 
Intravaginal  
 
Transdermal  
 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 
Oral  
 
Injectable  
Highly Effective Methods That Are User Independenta  
Failure rate of < 1% per year when used consistently and correctly. 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.  


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a 
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for study participants 
participating in clinical studies.  
b 
Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In this case, 2 highly effective methods of 
contraception should be utilized during the treatment period and for at least 3 months after the last 
dose of study intervention.  
 
Collection of Pregnancy Information: 
Details of this procedure are described in Section 8.3.5. 
Male participants with partners who become pregnant  
 The investigator (or qualified designee) will attempt to collect pregnancy 
information on any male participant’s female partner who becomes pregnant 
while the male participant is in this study. This applies only to male participants 
who receive study intervention. 
 After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator (or qualified designee) will record pregnancy 
information on the Pregnancy Form and submit it to the sponsor within 24 hours 
of learning of the partner’s pregnancy. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother 
and child will be forwarded to the sponsor. Generally, the follow-up will be no 
longer than 6 to 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.  
Female Participants who become pregnant  
 The investigator (or qualified designee) will collect pregnancy information on any 
female participant who becomes pregnant while participating in this study. 
Information will be recorded on the Pregnancy Form and submitted to the sponsor 
within 24 hours of learning of a participant's pregnancy. The participant will be 
followed to determine the outcome of the pregnancy. The investigator (or 
qualified designee) will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the sponsor. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any poststudy pregnancy-related SAE considered reasonably 
related to the study intervention by the investigator will be reported to the sponsor 
as described in Section 8.3.4. While the investigator is not obligated to actively 


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seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.  
 Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention or be withdrawn from the study. 
10.5 Appendix 5: Genetics 
PGx Research Objective 
The objective of the PGx research is to investigate a possible genetic relationship to 
handling or response to S-648414, or to advance understanding of disease biology (see 
Section 8.7). 
Informed Consent 
Participants in the PGx research must voluntarily sign a PGx ICF prior to the blood 
sample collection for PGx research, in addition to the informed consent for participating 
in the study body. Study participants who do not wish to participate in the PGx research 
may still participate in the clinical study.  
Management of Sample 
For the volume of blood sample to be collected, the time of sample collection, and the 
storage and shipping condition, see Section 8.7.  
The blood sample will be given a specific number to link the sample to study participant 
and protect personal information (ie, the sample will not be identified with participant 
personal information by de-identification). Direct personal identifiers (eg, name, address, 
social security number) will not be transferred to DNA banking facilities and PGx 
analysis sites.  
The sponsor will store extracted DNA samples in the DNA banking facility (BML, INC. 
in Japan) for up to 10 years after the study completion.  
Detailed procedures for sample collection, handling, labeling, storage, and shipping will 
be specified in a separate document. 
PGx Analysis 
A separate study protocol will be created to specify the details of the study plan and the 
site of the PGx analysis. The PGx research will be conducted after obtaining the approval 
from the ethics committee based on the committee’s review about the study’s ethics and 
scientific adequacy. Results for the PGx analysis will be reported in separate documents 
from the main study results.  
All results obtained from the samples will be kept confidential and, if published, all data 
will be displayed without any personal identifiers. The results of the PGx analysis will 
not be disclosed to the study participant to avoid disadvantage for the study participant or 


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his/her family due to misinterpretation of data which may be generated without assay 
validation to support clinical use. 
Study participants can request destruction of his/her blood sample and DNA whenever 
(even after the clinical study completes); however, the analyzed data including data from 
the study participant can still be evaluated after consent is withdrawn if PGx analysis has 
already been completed at the time of withdrawal of consent for PGx analysis.  
Study Participant Withdrawal 
As stated above, if study participants want to destroy his/her blood sample and DNA, the 
study participant can request it at any time (even after the clinical study completes).  
In addition, a study participant who has consented to participate in PGx research and has 
a sample collected for PGx research can withdraw from the clinical study for any reason. 
Regardless whether study participants withdrew the clinical study or not, their blood 
sample (DNA after extraction) is stored for the PGx research and is destroyed according 
to procedures on the destruction stated in the previous section. 
10.6 Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Phase 1 liver chemistry stopping criteria are designed to assure participant safety and to 
evaluate liver event etiology. 
Phase 1 Liver Chemistry Stopping Criteria and Follow-Up Assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute 
ALT ≥ 3 x ULN 
If ALT ≥ 3 x ULN AND bilirubin  2 x ULN (> 35% direct bilirubin) or INR 
> 1.5, report as a SAEa, b 
See additional actions and follow-up assessments below 
Required Actions and Follow-up Assessments  
Actions 
Follow-Up Assessments 
 
Immediately discontinue study intervention. 
 
Report the event to the sponsor’s medical 
monitor within 24 hours. 
 
Complete the Liver Event Form, and 
complete an SAE data collection tool if the 
event also met the criteria for an SAEb. 
 
Perform liver function follow-up assessments. 
 
Monitor the participant daily until liver 
function test abnormalities resolve, stabilize, 
or return to baseline (see MONITORING). 
MONITORING: 
If ALT ≥ 3 x ULN AND bilirubin  2 x ULN or 
INR > 1.5 
 
Viral hepatitis serologyc. 
 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminase 
values show downward trend. 
 
Obtain blood sample for PK analysis after 
the most recent dosed. 
 
Serum CPK and LDH. 
 
Fractionate bilirubin, if total bilirubin 
 2 x ULN. 
 
Complete blood count with differential to 
assess eosinophilia. 
 
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE eCRF. 


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 
Repeat liver function tests (include ALT, 
AST, ALP, bilirubin and INR) and perform 
liver function follow-up assessments within 
24 hours. 
 
Monitor participant twice weekly until liver 
function test abnormalities resolve, stabilize, 
or return to baseline. 
 
A specialist or hepatology consultation is 
recommended. 
If ALT ≥ 3 x ULN AND bilirubin < 2 x ULN 
and INR ≤ 1.5: 
 
Repeat liver function tests (include ALT, 
AST, alkaline phosphatase, bilirubin and 
INR) and perform liver function follow-up 
assessments within 24 to 72 hours. 
 
Monitor participants weekly until liver 
function abnormalities resolve, stabilize, or 
return to baseline. 
 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the concomitant medications eCRF. 
 
Record alcohol use on the liver event 
alcohol intake eCRF. 
 
 
If ALT ≥ 3 x ULN AND bilirubin  2 x ULN 
or INR > 1.5: 
 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total IgG or gamma globulins. 
 
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week [10]).  
 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete liver imaging and/or liver biopsy 
eCRFs. 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate 
transaminase; CPK = creatine phosphokinase; eCRF = electronic case report form; HPLC = high-
performance liquid chromatography; IgG = immunoglobulin G; IgM = immunoglobulin M; 
INR = international normalized ratio; LDH = lactate dehydrogenase; PK = pharmacokinetic; 
SAE = serious adverse event; ULN = upper limit of normal 
a. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study intervention if ALT  3 x ULN and 
bilirubin  2 x ULN. Additionally, if serum bilirubin fractionation testing is unavailable, record 
the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct 
bilirubin elevations suggesting liver injury.  
b. All events of ALT  3 x ULN and bilirubin  2 x ULN (> 35% direct bilirubin) or ALT 
 3 x ULN and INR > 1.5 may, if INR measured which may indicate severe liver injury (possible 
“Hy’s Law”) and must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). The INR stated threshold value will not apply to participants receiving anticoagulants.  
c. 
Includes Hepatitis A IgM antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody 
or monospot testing); and hepatitis E IgM antibody.  
d. PK sample may not be required for participants known to be receiving placebo or noncomparator 
interventions. Record the date/time of the PK blood sample draw and the date/time of the last 
dose of study intervention prior to the PK blood sample draw on the eCRF. If the date or time of 
the last dose is unclear, provide the participant’s best approximation. If the date/time of the last 
dose cannot be approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are in the Study 
Reference Manual. 
 
 


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10.7 Appendix 7: Abbreviations and Acronyms 
AE 
adverse event 
Aeu0-96 
cumulative amount of the drug excreted in urine 
during a given collection time interval from 0 to 96 
hours 
Aeu0-τ 
amount of drug excreted in urine over the dosing 
interval τ 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the concentration-time curve extrapolated 
from time zero to infinity 
AUC0-last 
area under the concentration-time curve from time 
zero to the time of the last quantifiable 
concentration after dosing 
AUC0-τ 
area under the concentration-time curve over the 
dosing interval τ 
AUCextr 
extrapolated percent of the area under the 
concentration-time curve from time zero to infinity 
AUMC0-inf 
area under the first moment curve extrapolated to 
infinity 
AV 
atrioventricular 
BID 
twice daily 
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
bpm 
beats per minute 
Cτ 
plasma concentration at the end of the dosing 
interval τ (24 hours)  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical 
Sciences 
CL/F 
apparent total clearance 
CLR 
renal clearance 
Cmax 
maximum plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CPK 
creatine phosphokinase 


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CRO 
contract research organization 
CRU 
clinical research unit 
CV 
coefficient of variation 
CYP3A 
cytochrome P450 3A 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
Feu 
fraction of dose excreted in urine 
Feu0-τ 
fraction of dose excreted in urine over the dosing 
interval τ 
Feu0-96 
fraction of dose excreted in urine from 0 to 96 hours 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GI 
gastrointestinal 
eGFR 
estimated glomerular filtration rate 
HED 
human equivalent dose 
HIPAA 
Health Information Portability and Accountability 
Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for 
Human Use  
IEC 
Independent Ethics Committee 
IN 
integrase 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LEDGF 
IN-lens epithelium-derived growth factor 
LDH 
lactate dehydrogenase 
MAD 
multiple ascending dose(ing) 
Mean 
arithmetic mean 
MDZ 
midazolam 
MRSD 
maximum recommended starting dose 
MRT 
mean residence time 


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N 
number of nonmissing observations 
NOAEL 
no observed adverse event level 
OTC 
over-the-counter 
oz. 
ounces 
PGx 
pharmacogenomic(s) 
PK 
pharmacokinetic(s) 
 
 
PR 
measure between beginning of P wave until 
beginning of QRS complex 
QC 
quality control 
QD 
once daily 
QRS 
combination of the Q, R, and S waves 
QT 
QT interval (measure between Q and T wave in 
heart’s electrical cycle) 
QTc 
corrected QT 
QTcI 
QTc individual 
QTcF 
Fridericia’s corrected QT 
QWBA 
quantitative whole body autoradiography 
R2 
coefficient of determination 
RR 
interval from the peak of one QRS complex to the 
next QRS peak  
SAD 
single ascending dose(ing) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOP 
standard operating procedure 
Study intervention 
S-648414 or placebo 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2,z 
terminal elimination half-life 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution in the terminal 
elimination phase 
WHO 
World Health Organization  
WOCBP 
woman of childbearing potential 
λz 
terminal elimination rate constant 
Δ 
change from baseline 
ΔΔ 
placebo-corrected change from baseline 


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10.8 Appendix 8: Protocol Amendment History 
Amendment 5 (06 May 2020) 
Overall Rationale for the Amendment: 
This amendment was considered necessary to allow the study to expand from a single 
center in the USA to a 2-center, 2-region study (USA and Japan) to enable enrollment of 
study participants into Part 3 of the study in either center depending on the risk\impact of 
coronavirus disease 2019 (COVID-19) around the time of enrollment. 
In addition, with this amendment the doses in Part 3 of the study were changed. Based on 
the unblinded results from Parts 1 and 2 of the study, it was determined that the overall 
safety profile of the doses evaluated to date was acceptable (see Investigator’s Brochure 
Version 2 Addendum 1 for results). An earlier protocol amendment (Amendment 3) was 
instituted to reduce the doses of S-648414 in Part 3 based on 3 study participants 
experiencing adverse events leading to study intervention discontinuation in the 50 mg 
multiple dose group during Part 2. A planned interim lock of Parts 1 and 2 showed that 
after unblinding, 2 of the study participants experiencing adverse events leading to 
discontinuation were on placebo (preferred terms iritis and allergic reaction). It was 
determined that it would be acceptable to increase the dose in Part 3 to doses that had 
originally been intended to be assessed (see Investigator’s Brochure Version 2 
Addendum 1 for further results). 
The cohorts affected by this change in dose included:  
 Group I changed from S-648414 30 mg (with and without dolutegravir) to 
S-648414 100 mg (with and without dolutegravir)  
 Group J changed from S-648414 50 mg (with and without dolutegravir) to 
S-648414 200 mg (with and without dolutegravir) 
A high-level description of the change(s) and brief scientific rationale for specific items 
are outlined in the following: 
Section(s) # and Name(s) 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Objective and Endpoints, 
Table 1-1 and Section 3 
Objectives and Endpoints, 
Table 3-1 
Part 3, added primary objective and 
endpoint: 
Objective: 
 To evaluate the safety and 
tolerability of S-648414 after 
administration of multiple oral doses 
of S-648414 in healthy adult study 
participants 
Endpoint: 
 The number and percentage of 
clinical and laboratory adverse 
events in study participants exposed 
to multiple doses of S-648414 
Safety and tolerability of 
S-648414 (100 mg and 
200 mg) are a primary 
objective, along with 
pharmacokinetics (PK) 


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Section(s) # and Name(s) 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, Overall 
Design and Section 4.1 
Overall Design 
Changed single center to multicenter 
(2 centers) 
Added a study center in Japan 
Section 1.1 Synopsis, Overall 
Design, Part 3, Table 1-4, 
Table 1-5, Section 1.4 
Overall Design, Table 4-3, 
Table 6-3, and Section 6.6.3 
Part 3 – Coadministration 
with Dolutegravir 
Changed dose Group I from 30 mg to 
100 mg 
 
Changed dose Group J from 50 mg to 
200 mg 
In the multiple-ascending dose 
portion of this study, 3 study 
participants in the 50 mg 
blinded group discontinued 
due to adverse events. Based 
on these blinded data, Groups I 
and J were previously 
amended to lower the dose for 
Group I to 30 mg and repeat 
the 50 mg exposure to gain 
further safety data at this dose 
in Group J. On subsequent 
unblinding, 2 of the 
3 discontinuations were 
placebo recipients and so 
50 mg was assessed as safe 
and escalation of the dose 
could be considered initially to 
100 mg, followed by 200 mg if 
the escalation criteria are met 
Section 1.1 Synopsis, Overall 
Design, Part 3, Section 4.1 
Overall Design, and 
Section 6.6.3 Part 3 – 
Coadministration with 
Dolutegravir 
Added safety review criteria for Part 3 
The investigator and sponsor 
will evaluate the results of the 
safety and tolerability of the 
100 mg group before 
proceeding to the 200 mg 
group 
Section 1.1 Synopsis, 
Inclusion Criteria and 
Section 5.1 Inclusion Criteria 
Modified inclusion criterion 1 to 
 clarify lower age (≥ 18 years in USA, 
≥ 20 years in Japan)  
 only include White or Black or 
African American study participants 
in Japan 
 Clarified lower age limit in 
Japan based on difference in 
adult definitions between 
USA and Japan 
 Restricted race in Japan to 
increase global consistency 
and comparability across 
results 
Section 2.2 Background 
Added “The study will also assess the 
safety and tolerability of multiple doses 
of S-648414 (100 mg and 200 mg) and 
the effect of these doses of S-648414 
on the PK of dolutegravir and the effect 
of dolutegravir (50 mg) on the PK of 
S-648414.” 
Clarified new dose groups for 
multiple doses of S-648414 
during Part 3 
Section 4.3 Justification for 
Dose 
Changed initial dose in Part 3 from 
30 mg/day to 100 mg/day and the 
subsequent dose from 50 mg/day to 
200 mg/day 
In the multiple-ascending dose 
portion of this study, 3 study 
participants in the 50 mg 
blinded group discontinued 
due to adverse events. Based 
on these blinded data, Groups I 
and J were previously 




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Amendment 4 (16 Mar 2020) 
Overall Rationale for the Amendment:  
Ocular adverse events were reported during Part 2 of the study and ophthalmological 
examinations were considered appropriate to be added to Part 3 of the study.  
A high-level description of the change(s) and brief scientific rationale for specific items 
are outlined in the following: 
Section(s) # and Name(s) 
Description of Change 
Brief Rationale 
Figure 1-4 and Figure 1-5, 
Section 8.2.5 Ophthalmological 
Examinations 
Added ophthalmological 
examinations on Admission Day 
(Day -1) and at Discharge (Day 29) 
of Part 3 
Added ophthalmological 
examinations to Part 3 based on 
recent ocular adverse events 
reported during Part 2 
Figure 1-4 
In footnotes d and f, deleted “and 
Follow-up visit” because this is not 
applicable to Period 1 of Part 3 
Minor editorial revision 
Section 4.3 Justification for 
Dose 
Added description of Part 3 
including administration with 
dolutegravir and planned starting 
and subsequent doses 
Added justification for dose in 
Part 3 
Section 5.3.1 Meals and 
Dietary Restrictions 
Clarified that study intervention in 
Part 3 (ie, Steps 9 and 10) should 
be administered 30 minutes after 
initiation of breakfast and no food 
should be allowed for 4 hours 
postdose 
Clarification 
Table 6-1 Study Intervention(s) 
Clarified that 240 mL of water 
should be administered with 
dolutegravir 
Clarification 
8.2.1 Physical Examinations, 
Figure 1-4, and Figure 1-5 
Clarified that symptom-focused 
physical examinations should be 
conducted for new or worsening 
adverse events/symptoms. 
Clarification 
 
 


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Amendment 3 (09 Feb 2020) 
Overall Rationale for the Amendment: 
As per Section 6.6.2 of the protocol, upon review of preliminary safety information from 
multiple-ascending dose (MAD) Group G (50 mg daily), the dose for subsequent MAD 
cohort (Group H) was adjusted to 30 mg daily with protocol amendment 3. Specifically, 
although the dose-escalation stopping criteria were not met (as described in Section 6.6.2 
of the protocol), there were 3 out of 10 (30%) study participants who received multiple 
doses of 50 mg (blinded study intervention) and had grade 2 treatment-related adverse 
events that led to discontinuation of study intervention. Subsequently, the dose was also 
decreased for the cohort examining the potential for a drug-drug interaction with 
dolutegravir.  
The cohorts affected by this change in dose included:  
 Group H changed from S-648414 200 mg to S-648414 30 mg  
 Group I changed from S-648414 200 mg (with and without dolutegravir) to 
S-648414 30 mg (with and without dolutegravir) 
A high-level description of the change(s) and a brief scientific rationale for specific items 
is outlined in the following: 
Section(s) # and Name(s) 
Description of Change 
Brief Rationale 
Synopsis, Overall Design Part 2 and 
Table 1-5, Section 2.2 Background, 
Section 4.1 Overall Design, 
Table 4-2, Section 4.3 Justification 
for Dose, Table 6-3, Section 6.6.2 
Part 2- Multiple Dosing, 
Section 6.6.3 Part 3 – 
Coadministration with Dolutegravir 
Changed dose Group H 
from 200 mg to 30 mg. 
 
Changed dose Group I 
from 200 mg to 30 mg. 
Treatment-related adverse events 
were observed with multiple doses 
of 50 mg (Group G) in 30% of 
subjects; subsequent cohorts with 
multiple doses were decreased to 
30 mg (Groups H and I). 
Synopsis, Overall Design, Part 2, 
Table 1-4, Table 1-5, Section 4.1 
Overall Design, Table 4-3, Table 6-3, 
Section 6.6.3 Part 3 – 
Coadministration with Dolutegravir, 
Section 9.5 Interim Analysis 
Deleted text pertaining to 
interim review of Group I. 
No interim review is needed now 
that Group I changed from 200 mg 
to 30 mg. Interaction with 
dolutegravir in Part 3 will be 
assessed with 2 planned doses 
(30 mg in Group I and 50 mg in 
Group J). 
Synopsis, Study Intervention Groups 
and Duration 
Deleted 100 mg tablets 
from Parts 2 and 3. 
Based on dose change from 200 mg 
to 30 mg, only 10 mg tablets will be 
used in Part 2 (Groups G and H) and 
Part 3 (Groups I and J). 
8.3.3 Follow-up of Adverse Events 
and Serious Adverse Events 
Added that all adverse 
events (AEs) will be 
followed until resolution, 
stabilization, the event is 
otherwise explained, or 
the participant is lost to 
follow-up. Previously it 
Treatment-related adverse events 
were observed in Group G (multiple 
doses of 50 mg). Based on Group G 
data, all AEs will be followed until 
resolution, stabilization or until the 
event is otherwise explained to 
monitor study safety. 


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Section(s) # and Name(s) 
Description of Change 
Brief Rationale 
was only serious adverse 
events (SAEs) and non-
serious AEs of special 
interest. 
Figure 1-3 and Section 8.7 Genetics 
Clarified collection of 
pharmacogenomics 
sample should be 
collected on Admission 
Day, which is Day -1 in 
Part 1 and Day -3 in 
Part 2. 
Clarification  
Figure 1-3 
In footnote d, clarified 
that vital signs should be 
collected on Admission 
Day (Day -3). 
Clarification 
 
Amendment 2 (27 Jan 2020)  
Overall Rationale for the Amendment: 
The primary reason for protocol amendment 2 was to add a third part (Part 3) to the 
study, where the effect of S-648414 on the PK) of dolutegravir and the effect of 
dolutegravir on the PK of S-648414 will be studied. 
A high-level description of the change(s) and a brief scientific rationale for specific items 
is outlined in the following: 
Section(s) # and Name 
Description of Change 
Brief Rationale 
Title Page 
Added “; and A Phase 1 Open-Label Study 
to Assess the Effect of S-648414 on the 
Pharmacokinetics of Dolutegravir and the 
Effect of Dolutegravir on the 
Pharmacokinetics of S-648414 in Healthy 
Adult Study Participants (Part 3)” 
To add Part 3 
Updated to Amendment Number 2. 
Minor editorial revision 
1.1. Synopsis, Protocol 
Title 
Added “; and A Phase 1 Open-Label Study 
to Assess the Effect of S-648414 on the 
Pharmacokinetics of Dolutegravir and the 
Effect of Dolutegravir on the 
Pharmacokinetics of S-648414 in Healthy 
Adult Study Participants (Part 3)” 
To add Part 3 
1.1 Synopsis, Rationale 
Added the effect of S-648414 on the PK of 
dolutegravir and the effect of dolutegravir 
on the PK of S-648414. 
To add Part 3 
1.1 Synopsis, Objectives 
and Endpoints, Table 1-1 
Objectives and Endpoints 
and 3 Objectives and 
Endpoints, Table 3-1 
Objectives and Endpoints 
Added primary objectives: to evaluate the 
effect of S-648414 on the PK of 
dolutegravir and the effect of dolutegravir 
on the PK of S-648414 and to add primary 
endpoints: Cmax, Tmax, Cτ, AUC, and CL/F in 
Part 3. 
Added primary and 
secondary objectives and 
endpoints for Part 3 


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Section(s) # and Name 
Description of Change 
Brief Rationale 
Added secondary objective: to evaluate the 
safety and tolerability of S-648414 
coadminstered with dolutegravir and to add 
secondary endpoints of number and 
percentage of clinical and laboratory 
adverse events in Part 3. 
Added definition for Cτ in the footnotes. 
Minor editorial revision 
1.1 Synopsis, Overall 
Design 
Added the effect of S-648414 on the PK of 
dolutegravir and the effect of dolutegravir 
on the PK of S-648414. 
To add Part 3 
Updated table and figure cross reference 
numbering (changed Table 1-3 to Table 1-5, 
changed Figure 1-1 to Figure 1-2, and 
Figure 1-2 to Figure 1-3), added “of” in 
header of Table 1-2 and Table 1-3. 
Minor editorial revisions 
Added study design details for Part 3 
including open-label, non-randomized, 
1-sequence, 3-period study. Added study 
period and treatment details for Part 3. 
Added Table 1-4 Part 3 Treatment 
Schedule. 
To add study design 
details for Part 3 
1.1 Synopsis, Inclusion 
Criteria and 5.1 Inclusion 
Criteria  
Criterion 4, clarified administration of 
“study intervention”. 
Minor editorial revision 
Criterion 4, added details that clinical 
evaluations can be repeated (for 
confirmatory purposes or if additional 
information is required to assess study 
participant’s eligibility) at the discretion of 
the investigator; repeated procedures must 
be performed within the same Screening 
window. 
To add details to allow for 
repeat evaluations during 
Screening 
1.1 Synopsis, Exclusion 
Criteria and 5.2 Exclusion 
Criteria 
Criterion 23, clarified amount of blood 
donated as > 500 mL. 
Minor editorial revision 
1.1 Synopsis, Number of 
Study Participants and 9.2 
Sample Size 
Determination  
Added “28 healthy adult study participants 
in Part 3” 
To add number of study 
participants for Part 3 
1.1 Synopsis, Study 
Intervention, Groups and 
Duration 
Added “S-648414 tablets 10 mg or 100 mg 
in the fed state (Groups I and J)” 
To add dose strength in 
Part 3 
1.1 Synopsis, Other 
Treatment, Dose, and 
Mode of Administration 
Added “Dolutegravir 50-mg tablet, oral 
administration in the fed state” 
To add other treatment 
required during Part 3 
1.1 Synopsis, Duration of 
Study Intervention 
Added “Multiple doses of dolutegravir once 
daily during Period 1, multiple doses of 
S-648414 once daily during Period 2, and 
multiple doses of S-648414 coadministered 
with dolutegravir once daily during 
Period 3.” 
To add study intervention 
during Part 3 


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Section(s) # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, Study 
Duration for Individual 
Study Participants 
(Includes Screening, 
Treatment and Follow-up 
Period) 
Added 5 to 9 weeks for Part 3. 
To add duration during 
Part 3 
1.1 Synopsis, 
Pharmacokinetic 
Assessments 
Added PK assessments (Cmax, Tmax, Cτ, 
AUC0-τ, and CL/F) for Part 3.  
To add PK assessments 
for Part 3 
1.1 Synopsis, Safety 
Assessments 
Clarified that ophthalmological 
examinations are collected in Parts 1 and 2. 
Ophthalmological 
examinations not 
collected in Part 3 
1.1 Synopsis, Statistical 
Methods 
Added details for PK analysis (ie, ANOVA 
model) for Part 3. 
To add PK statistical 
methods for Part 3 
Clarified that ophthalmological 
examinations are collected in Parts 1 and 2. 
Ophthalmological 
examinations not 
collected in Part 3 
1.1 Synopsis, Table 1-5 
Updated table numbering from Table 1-4 to 
Table 1-5. 
Minor editorial revisions 
Added rows and footnotes for Groups I and 
J. 
To add Part 3 
1.2 Schema 
Added “Figure 1-1 Study Schematic -
Part 3” and updated figure cross referencing 
(updated Figure 1-1 to Figure 1-2, 
Figure 1-2 to Figure 1-3) and added cross 
referencing for Part 3 (Figure 1-4 and 
Figure 1-5). 
To add figure and minor 
editorial changes 
1.3 Schedule of Activities 
Part 1, Figure 1-2 
Updated figure numbering from Figure 1-1 
to Figure 1-2. 
Minor editorial revision. 
Changed collection of PGx sample from 
predose on Day 1 to Admission Day 
(Day -1) 
For consistency across 
Parts 1 to 3 of the study 
Footnote h - changed optometrist to 
ophthalmologist. 
Clarified specialist 
1.3 Schedule of Activities 
Part 2, Groups G and H, 
Figure 1-3 
Updated figure numbering from Figure 1-2 
to Figure 1-3. 
Corrected grammar in footnote i. 
Minor editorial revision 
Changed collection of PGx sample from 
predose on Day 1 to Admission Day 
(Day -1) 
For consistency across 
Parts 1 to 3 of the study 
Deleted (S-648414 or placebo) after 
intervention. 
Minor editorial revision 
In footnote g, changed optometrist to 
ophthalmologist. 
Clarified specialist 
1.3 Schedule of Activities, 
Figure 1-4 and Figure 1-5 
Added Figure 1-4 Schedule of Activities – 
Part 3, Period 1, Groups I and J and 
Figure 1-5 Schedule of Activities – Part 3, 
Periods 2 and 3, Groups I and J. 
To add schedule of 
activities for Part 3 


S-648414 
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Clinical Study Protocol: 1908T0911, Amendment 6 
17 Jun 2020 
 _____________________________________________________________________________________  
 
Confidential 
Page 107 of 112 
Section(s) # and Name 
Description of Change 
Brief Rationale 
2.1 Study Rationale 
Added “as well as the effect on PK of 
dolutegravir and the effect of dolutegravir 
on PK of S-648414.” 
To add Part 3 
4.1 Overall Design 
Updated figure cross reference numbering 
(changed Figure 1-1 to Figure 1-2, and 
Figure 1-2 to Figure 1-3). 
Minor editorial revisions 
4.1 Overall Design, Part 3 
and Table 4-3 
Added study design, treatment details, and 
Part 3 Treatment Schedule for Part 3. 
To add Part 3 
4.2 Scientific Rationale for 
Study Design 
Added details for Part 3. 
To add Part 3 
5.4 Screen Failures 
Deleted paragraph regarding screen failures.  
Deleted text and revised 
Inclusion Criterion 4 in 
Sections 1.1 and 5.1, 
which allows for repeated 
assessments 
6.1 Study Intervention(s) 
Administered, Table 6-1 
Study Intervention(s) 
Clarified unit dose of midazolam is 
2 mg/mL and dosage level is 5 mg 
Minor editorial revision 
Added “1 bottle per box” for S-648414 and 
placebo 
Clarified that packaging 
includes 1 bottle per box 
Changed manufacturer for midazolam. 
Updated to indicate 
generic versions are 
acceptable 
Added study intervention details for 
dolutegravir. 
To add dolutegravir for 
Part 3 
6.1 Study Intervention (s) 
Administered, Table 6-2 
Number of Tablets 
(S-648414 or Placebo) per 
Dose Group 
Added or “(S-648414 or Placebo)” to title. 
Minor editorial revision 
6.2 Preparation/Handling/ 
Storage/Accountability of 
Study Intervention 
Item 1, deleted “and protected from light.” 
Study intervention does 
not need to be protected 
from light. 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding; 
7.1 Discontinuation of 
Study Intervention; 
7.2 Study Participant 
Discontinuation/ 
Withdrawal from the 
Study; 8 Study 
Assessments and 
Procedures; 8.2 Safety 
Assessments; 
8.2.4 Clinical Safety 
Laboratory Assessments; 
8.2.5 Ophthalmological 
Examinations 
Updated figure cross reference numbering 
(changed Figure 1-1 to Figure 1-2, and 
Figure 1-2 to Figure 1-3), and added cross-
references for Figure 1-4 and Figure 1-5.  
Minor editorial revisions 


S-648414 
Shionogi Inc. 
Clinical Study Protocol: 1908T0911, Amendment 6 
17 Jun 2020 
 _____________________________________________________________________________________  
 
Confidential 
Page 108 of 112 
Section(s) # and Name 
Description of Change 
Brief Rationale 
6.6 Dose Modification of 
Study Intervention, 
Table 6-3 Sequence of 
Steps 
Added rows and footnotes for Groups I and 
J. 
To add Part 3 
6.6.3 Part 3 – 
Coadministration with 
Dolutegravir 
Added treatment details for Groups I and J. 
To add Part 3 
7.1 Discontinuation of 
Study Intervention 
Clarified that this text pertaining to 
discontinuation of study intervention 
applies to Part 2 and Part 3 
To add Part 3 
8.2.3 Electrocardiograms 
Changed to clarify only Holter equipment 
will be supplied by ERT. 
Minor clarification 
8.2.3.2 Expert-Precision 
QT Analysis 
In second paragraph, changed “cardiologist” 
to “cardiac safety specialist”. 
Minor clarification 
8.2.5 Ophthalmological 
Examinations 
Changed optometrist to ophthalmologist. 
Clarified specialist 
8.3.1 Time Period and 
Frequency for Collecting 
Adverse Events and 
Serious Adverse Event 
Information, 8.3.3 Follow-
up of Adverse Events and 
Serious Adverse Events, 
8.3.4 Regulatory Reporting 
Requirements for Serious 
Adverse Events, 
8.4 Special Situations – 
Abuse, Misuse, Overdose, 
and Medication Error, 
10.3 Appendix 3: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting 
Modified wording to indicate that SAEs 
will be recorded “in the eCRF” and that the 
investigator or “qualified designee” can 
submit AE/SAE initial or follow-up 
information. 
Clarified that AE/SAE 
reports and updates can be 
submitted by the 
investigator or qualified 
designee. 
8.3.1 Time Period and 
Frequency for Collecting 
Adverse Events and 
Serious Adverse Event 
Information 
Added paragraph “Investigators or qualified 
designees are not obligated to actively seek 
AEs or SAEs after conclusion of the study 
participation. However, if the investigator 
or qualified designee learns of any SAE, 
including a death, at any time after a 
participant is no longer in the study, and the 
investigator or qualified designee considers 
the event to be reasonably related to the 
study treatment or study participation, the 
investigator or qualified designee must 
promptly notify the sponsor via phone, 
e-mail, or fax (see Section 10.3 
[Appendix 3]). Investigator assessment of 
causality must be included with all SAEs 
reported to the sponsor. Serious adverse 
events with missing investigator causality 
To add instructions for 
collection of SAEs after 
conclusion of study 
participation 


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Clinical Study Protocol: 1908T0911, Amendment 6 
17 Jun 2020 
 _____________________________________________________________________________________  
 
Confidential 
Page 109 of 112 
Section(s) # and Name 
Description of Change 
Brief Rationale 
will be followed up by the CRO urgently 
until response is provided to the sponsor.” 
8.5 Pharmacokinetics 
Updated figure cross reference numbering 
(changed Figure 1-1 to Figure 1-2, and 
Figure 1-2 to Figure 1-3). 
Minor editorial revisions 
Added amount of plasma required for 
Part 3. 
To add Part 3 
Clarified that samples are to be shipped to 
bioanalytical laboratory at 
 
Minor clarification 
8.7 Genetics 
Second paragraph, changed collection of 
blood sample from Day 1 to Day -1. 
Changed to match 
schedule of assessments 
8.8 Biomarkers 
Updated figure cross reference numbering 
(changed Figure 1-2 to Figure 1-3), 
corrected maximum storage requirements to 
-85ºC. 
Added shipping address for biomarkers. 
Minor editorial revisions 
9.1 Statistical Hypotheses 
Added effect on PK of dolutegravir and 
effect of dolutegravir on PK of S-648414. 
To add Part 3 
9.3 Populations for 
Analyses 
Added dolutegravir to definition of PK 
concentration population. 
To add Part 3 
9.4 Statistical Analyses 
For the SAP, deleted “have a version 1.0 
available by first patient randomized, and” 
Clarified that SAP will 
finalized before 
unblinding/database lock 
but not before first patient 
randomized. 
9.4.3 Safety Analyses, 
Adverse event  
Clarified study intervention definition from 
S-648414 or placebo to S-648414, 
midazolam, dolutegravir, or placebo. 
To clarify study 
intervention definition for 
AEs leading to study 
intervention withdrawal 
9.4.4.1 Pharmacokinetic 
Analyses 
Added primary endpoints of effect of 
S-648414 on PK of dolutegravir and effect 
of dolutegravir on PK of S-648414. 
To add Part 3 
9.4.4.1.1 Plasma and Urine 
Concentration 
Added “and dolutegravir” and “and in 
Part 3 achievement of steady state for 
plasma S-648414 and dolutegravir.” 
To add Part 3 
9.4.4.1.2 Pharmacokinetic 
Parameters 
Added “and dolutegravir” 
Added PK parameters and definitions for 
Part 3. 
To add Part 3 
9.4.4.1.8 Effect of 
S-648414 on the 
Pharmacokinetics of 
Dolutegravir 
Added statistical analysis details for the 
effect of S-648414 on the PK of 
dolutegravir. 
To add Part 3 
9.4.4.1.9 Effect of 
Dolutegravir on the 
Pharmacokinetics of 
S-648414 
Added statistical analysis details for the 
effect of dolutegravir on the PK of 
S-648414. 
To add Part 3 


S-648414 
Shionogi Inc. 
Clinical Study Protocol: 1908T0911, Amendment 6 
17 Jun 2020 
 _____________________________________________________________________________________  
 
Confidential 
Page 110 of 112 
Section(s) # and Name 
Description of Change 
Brief Rationale 
9.5 Interim Analyses 
Added “To assist with the evaluation and 
dose selection for the S-648414 Proof of 
Concept study, the sponsor will be 
unblinded after the completion of Part 2 and 
an evaluation of safety and PK data from 
Parts 1 and 2 will be conducted. 
To add unblinded 
analyses by the sponsor 
after completion of Part 2 
Added “For open-label Part 3, Group J will 
receive 50 mg of S-648414 and will only be 
conducted if relevant interaction is observed 
with dolutegravir and S-648414 based on 
interim review of Group I (see Section 6.6.3 
for Part 3).” 
To add Part 3 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Changed “central” to “local” and deleted 
second bullet because not relevant as not 
using a central laboratory. 
Clarification that local 
laboratory is being used 
during the study and not a 
central laboratory 
10.3 Appendix 3: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up and 
Reporting 
Modified last bullet in Follow-up of AEs 
and SAEs information to indicate that SAE 
information is due to the sponsor within 
24 hours of awareness. Clarified that SAE 
information is to be submitted by the 
investigator “or qualified designee”  
Changed “Shionogi” to “sponsor” for the 
SAE data collection. 
Clarified that SAE 
updates can be submitted 
by the investigator or 
qualified designee and 
that SAE information is to 
be submitted within 
24 hours of awareness 
Added section for “SAE Reporting to 
Shionogi via Paper SAE Form (if EDC is 
unavailable)” 
Facsimile transmission of the SAE paper 
form is the preferred method to transmit this 
information to the medical monitor. 
In rare circumstances and in the absence of 
facsimile equipment, notification by 
telephone is acceptable with a copy of the 
SAE paper form sent by overnight mail or 
courier service. 
Initial notification via telephone does not 
replace the need for the investigator (or 
qualified designee) to complete and sign the 
SAE paper form within the designated 
reporting time frames. 
Added details for 
reporting SAEs to 
Shionogi via paper form if 
EDC is unavailable 
10.4 Appendix 4: 
Contraceptive Guidance 
and Collection of 
Pregnancy Information 
Clarified that collection and reporting of 
pregnancy information can be made by 
investigator or “qualified designee” 
Clarification that 
investigator or qualified 
designee can collect and 
report pregnancy 
information 
10.6 Appendix 6: Liver 
Safety: Suggested Actions 
and Follow-up 
Assessments 
Clarified that events should be reported to 
the sponsor “medical monitor” 
Minor clarification 


S-648414 
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Clinical Study Protocol: 1908T0911, Amendment 6 
17 Jun 2020 
 _____________________________________________________________________________________  
 
Confidential 
Page 111 of 112 
Section(s) # and Name 
Description of Change 
Brief Rationale 
10.7 Appendix 7: 
Abbreviations and 
Acronyms 
Added Cτ and corresponding definition. 
Added based on Part 3 
10.8 Appendix 8: Protocol 
Amendment History 
Added rationale and list of changes for 
Amendment 1 
Added protocol 
amendment history for 
Amendment 1 
Amendment 1 (23 Dec 2019)  
Overall Rationale for the Amendment: 
The primary reason for protocol amendment 1 was to modify the dose in Groups G and H 
in Part 2 based on preliminary data from Groups A, B, C, and D of this study. 
Human pharmacokinetic data from single ascending dose (SAD) cohorts 10 mg through 
250 mg demonstrated higher exposures than predicted and no safety concerns were 
identified.  
Based on these data, proposed doses of 100 mg and 300 mg for the multiple ascending 
dose (MAD) cohorts were reduced to 50 mg and 200 mg. The 50 mg and 200 mg doses 
are predicted to achieve sufficient exposures for anti-viral effect.  
A high-level description of the change(s) and a brief scientific rationale for specific items 
is outlined in the following: 
Section(s) # and Name(s) 
Description of Change 
Brief Rationale 
Synopsis, Overall Design 
Part 2, Table 1-3, and 
Table 1-4 
Section 4.1 Overall Design, 
Table 4-2, Section 4.3, 
Table 6-1, Table 6-2, 
Table 6-3, Section 6.6.2 
Changed dose Group G from 100 mg to 50 mg 
Changed dose Group H from 300 mg to 
200 mg 
Although no safety 
concerns were 
identified, doses were 
decreased based on 
higher exposures than 
predicted in Groups A, 
B, C, and D of this 
study. 
Synopsis, Test Drug, Dose, 
and Mode of Administration 
Part 2 – changed 100 mg tablets in Groups G 
and H to 10 mg or 100 mg tablets 
10 mg tablet added 
since Group G was 
changed from 100 mg to 
50 mg. 
 


S-648414 
Shionogi Inc. 
Clinical Study Protocol: 1908T0911, Amendment 6 
17 Jun 2020 
 _____________________________________________________________________________________  
 
Confidential 
Page 112 of 112 
11. 
REFERENCES 
1. Christ F and Debyser Z. The LEDGF/p75 integrase interaction, a novel target for 
anti-HIV therapy. Virology. 2013;435:102-9. 
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use 
of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health 
and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/ 
AdultandAdolescentGL.pdf. Accessed 02 Jun 2019. 
3. Palella FJ Jr, Chmiel JS, Moorman AC, et al. Durability and predictors of success of 
highly active antiretroviral therapy for ambulatory HIV-infected patients. AIDS. 
2002;16(12):1617–26. 
4. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on 
combination antiretroviral therapy in high-income countries: a collaborative analysis 
of 14 cohort studies. Lancet. 2008;372(9635) 293-9. 
5. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early 
antiretroviral therapy. N Engl J Med. 2011;365(6):493-505. 
6. Johnson JA, Li JF, Wei X, et al. Minority HIV-1 drug resistance mutations are 
present in antiretroviral treatment-naïve populations and associate with reduced 
treatment efficacy. PLoS Med. 2008;5(7):e158. doi: 10.1371/journal.pmed.0050158. 
7. Detels R, Muñoz A, McFarlane G, et al. Effectiveness of potent antiretroviral therapy 
on time to AIDS and death in men with known HIV infection duration. Multicenter 
AIDS Cohort Study Investigators. JAMA. 1998;280(17):1497-503. 
8. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality 
among patients with advanced human immunodeficiency virus infection. HIV 
Outpatient Study Investigators. N. Engl. J Med. 1998;338(13):853–60. 
9. Abgrall S, Ingle SM, May MT, et al. Durability of first ART regimen and risk factors 
for modification, interruption or death in HIV-positive patients starting ART in 
Europe and North America 2002–2009. AIDS. 2013;27(5):803–13. 
10. James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of Acetaminophen-Adduct 
in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab 
Dispos. 2009;37:1779-84. 
11. Dolutegravir [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2019. 
 



SAP_001.pdf: 
 
Shionogi Study Title: 
A Phase 1, Randomized, Double-Blind, Single-
Ascending-Dose, and Food Effect Study to Assess 
the Safety, Tolerability, Ventricular Repolarization, 
and Pharmacokinetics of S-648414 in Healthy Adult 
Study Participants (Part 1); A Phase 1, Randomized, 
Double-Blind, Multiple-Ascending-Dose Study to 
Assess the Safety, Tolerability, and 
Pharmacokinetics of S-648414 and A Drug-Drug 
Interaction Study with the CYP3A Substrate, 
Midazolam, in Healthy Adult Study Participants 
(Part 2); and A Phase 1 Open-Label Study to Assess 
the Effect of S-648414 on the Pharmacokinetics of 
Dolutegravir and the Effect of Dolutegravir on the 
Pharmacokinetics of S-648414 in Healthy Adult 
Study Participants (Part 3) 
Shionogi Study Number: 
1908T0911 
ClinicalTrials.gov 
Registration No. 
NCT04147715 
Study Document 
Statistical Analysis Plan Version 4 
10 Aug 2020 
 
 
History of Statistical Analysis Plan Amendments 
 
Version 1 (Original) 
22 Nov 2019 
Version 2 
3 Apr 2020 
 Version 3 
10 Apr 2020 
 Version 4 
10 Aug 2020 
Revisions to Version 1, 2, 3 and 4 are documented in Version 4 
 


Shionogi, Inc. 
 
Final Statistical Analysis Plan, Version 4.0 
 
Protocol: 1908T0911 
 
Date Issued: 10AUG2020 
 
Confidential 
 
 
 
 
 
 
 
 
 
Shionogi, Inc. 
 
1908T0911 
 
A Phase 1, Randomized, Double-Blind, Single-Ascending-Dose, and Food 
Effect Study to Assess the Safety, Tolerability, Ventricular Repolarization, 
and Pharmacokinetics of S-648414 in Healthy Adult Study Participants (Part 
1); A Phase 1, Randomized, Double-Blind, Multiple-Ascending-Dose Study to 
Assess the Safety, Tolerability, and Pharmacokinetics of S-648414 and A 
Drug-Drug Interaction Study with the CYP3A Substrate, Midazolam, in 
Healthy Adult Study Participants (Part 2); and A Phase 1 Open-Label Study 
to Assess the Effect of S-648414 on the Pharmacokinetics of Dolutegravir and 
the Effect of Dolutegravir on the Pharmacokinetics of S-648414 in Healthy 
Adult Study Participants (Part 3) 
 
 
10AUG2020 
 
Final Statistical Analysis Plan Amendment 3 
 
Version 4.0 
 
Prepared by:  
 
 
 
 
 
 
 
 
 
 


Shionogi, Inc. 
 
       Final Statistical Analysis Plan, Version 4.0 
 
Protocol: 1908T0911 
 
Date Issued: 10AUG2020 
 
  
 
 
 
II
TABLE OF CONTENTS 
DOCUMENT HISTORY ........................................................................................................... IV 
LIST OF ABBREVIATIONS ..................................................................................................... V 
1. 
INTRODUCTION............................................................................................................. 7 
2. 
OBJECTIVES ................................................................................................................... 7 
2.1. 
PART 1 OBJECTIVES ................................................................................................. 7 
2.2. 
PART 2 OBJECTIVES ................................................................................................. 8 
2.3. 
PART 3 OBJECTIVES ................................................................................................. 8 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 8 
3.1. 
OVERALL STUDY DESIGN AND PLAN ....................................................................... 8 
3.1.1. 
Part 1 Overall Study Design and Plan ..................................................................... 9 
3.1.2. 
Part 2 Overall Study Design and Plan ................................................................... 10 
3.1.3. 
Part 3 Overall Study Design and Plan ................................................................... 11 
3.2. 
STUDY ENDPOINTS ................................................................................................. 12 
3.2.1. 
Part 1 Study Endpoints ........................................................................................... 12 
3.2.2. 
Part 2 Study Endpoints ........................................................................................... 13 
3.2.3. 
Part 3 Study Endpoints ........................................................................................... 13 
4. 
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 13 
4.1. 
SAMPLE SIZE .......................................................................................................... 14 
4.2. 
RANDOMIZATION, STRATIFICATION, AND BLINDING ............................................ 14 
4.3. 
ANALYSIS POPULATIONS ........................................................................................ 15 
5. 
SUBJECT DISPOSITION ............................................................................................. 15 
5.1. 
SUBJECT DISPOSITION ............................................................................................ 16 
5.2. 
PROTOCOL DEVIATIONS ........................................................................................ 16 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 16 
6.1. 
DEMOGRAPHICS ..................................................................................................... 16 
6.2. 
MEDICAL HISTORY ................................................................................................ 16 
6.3. 
INCLUSION AND EXCLUSION CRITERIA ................................................................. 16 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 17 
7.1. 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................... 17 
7.1.1. 
Prior Medications ................................................................................................... 17 
7.1.2. 
Concomitant Medications ....................................................................................... 17 
7.2. 
MEDICAL OR SURGICAL TREATMENT PROCEDURES ............................................ 17 
7.3. 
STUDY INTERVENTION ADMINISTRATION ............................................................. 17 
7.4. 
MEALS .................................................................................................................... 17 
8. 
PHARMACOKINETIC ANALYSIS ............................................................................ 17 
8.1. 
PHARMACOKINETIC SAMPLE CONCENTRATIONS ................................................. 17 
8.2. 
PHARMACOKINETIC PARAMETERS ........................................................................ 20 
8.3. 
DOSE PROPORTIONALITY ASSESSMENTS .............................................................. 25 


Shionogi, Inc. 
 
       Final Statistical Analysis Plan, Version 4.0 
 
Protocol: 1908T0911 
 
Date Issued: 10AUG2020 
 
  
 
 
 
III
8.4. 
DOSE INDEPENDENCY ASSESSMENTS ..................................................................... 26 
8.5. 
FOOD EFFECT ASSESSMENT ................................................................................... 26 
8.6. 
ACCUMULATION ASSESSMENT ............................................................................... 27 
8.7. 
EFFECT OF S-648414 ON THE PHARMACOKINETICS OF MIDAZOLAM .................. 27 
8.8. 
EFFECT OF S-648414 ON THE PHARMACOKINETICS OF DOLUTEGRAVIR ............ 28 
8.9. 
EFFECT OF DOLUTEGRAVIR ON THE PHARMACOKINETICS OF S-648414 ............ 29 
9. 
SAFETY ANALYSIS...................................................................................................... 29 
9.1. 
ADVERSE EVENTS ................................................................................................... 29 
9.1.1. 
Incidence of Adverse Events ................................................................................... 30 
9.1.2. 
Relationship of Adverse Events to Study Intervention ............................................ 31 
9.1.3. 
Severity of Adverse Event........................................................................................ 31 
9.1.4. 
Serious Adverse Events ........................................................................................... 31 
9.1.5. 
Adverse Events of Special Interest .......................................................................... 32 
9.1.6. 
Adverse Events Leading to Study Discontinuation ................................................. 32 
9.2. 
CLINICAL LABORATORY EVALUATIONS ............................................................... 32 
9.3. 
VITAL SIGN MEASUREMENTS ................................................................................ 34 
9.4. 
ELECTROCARDIOGRAM .......................................................................................... 34 
9.5. 
OPHTHALMOLOGICAL EXAMINATIONS ................................................................. 35 
9.6. 
PHYSICAL EXAMINATION ....................................................................................... 35 
9.7. 
LIVER EVENTS ........................................................................................................ 35 
9.8. 
BIOMARKERS SAMPLE COLLECTION ..................................................................... 35 
10. 
INTERIM ANALYSIS ................................................................................................... 35 
11. 
CHANGE IN PLANNED ANALYSIS .......................................................................... 36 
12. 
APPENDIX ...................................................................................................................... 37 
12.1. 
SCHEDULE OF ASSESSMENTS ................................................................................. 37 
TABLE 12.1.1: SCHEDULE OF ACTIVITIES FOR PART 1 .............................................. 37 
TABLE 12.1.2: SCHEDULE OF ACTIVITIES FOR PART 2 .............................................. 41 
TABLE 12.1.3.1: SCHEDULE OF ACTIVITIES – PART 3, PERIOD 1, GROUPS I AND J
........................................................................................................................................... 45 
TABLE 12.1.3.2: SCHEDULE OF ACTIVITIES – PART 3, PERIOD 2 AND 3, GROUPS I 
AND J ............................................................................................................................... 48 
12.2. 
SEQUENCE OF STEPS............................................................................................... 51 
 


Shionogi, Inc. 
 
       Final Statistical Analysis Plan, Version 4.0 
 
Protocol: 1908T0911 
 
Date Issued: 10AUG2020 
 
  
 
 
 
IV
Document History 
Version 
Date 
Changes 
1.0 
22NOV2019 
Original version 
2.0 
03APR2020 
1) Protocol Version change from Version original dated 30 
July 2019 to Version Amendment 3 dated 09 Feb 2020. 
2) Part 3 was added. 
3) Part 2 dose were updated from Group G 100mg and 
Group H 300 mg to Group G 50 mg and Group H 30 
mg. 
4) Section 4.3: Analysis Populations were updated. 
5) Section 9.3: the summary method for 3 consecutive 
readings for blood pressure was added 
6) Pharmacogenomics Sample Collection were deleted 
from Section 9.8 
3.0 
10APR2020 
1) Section 9.1: Additional Ocular Adverse Events of 
Special Interest were added 
4.0 
10AUG2020 
1) Section 2.3, Part 3 Objectives updated per Protocol 
Amendment 6 
2) Section 3.1.3 Part 3 Overall Study Design, Days 9 to 13, 
changed from outpatient to either inpatient or outpatient 
per Protocol Amendment 6 
3) The dose for Groups I and J changed from 30 mg and 50 
mg to 100 mg and 200 mg per Protocol Amendment 6 
 
 
 


Shionogi, Inc. 
 
       Final Statistical Analysis Plan, Version 4.0 
 
Protocol: 1908T0911 
 
Date Issued: 10AUG2020 
 
  
 
 
 
V 
List of Abbreviations 
AE 
adverse event 
Aeux-y 
amount of the drug excreted in urine during a given collection time interval from x to y 
hours  
Aeu0-τ 
amount of drug excreted in urine over the dosing interval τ 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the concentration-time curve extrapolated from time zero to infinity 
AUC0-last 
area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration after dosing 
AUC0-τ 
area under the concentration-time curve over the dosing interval τ 
AUCextr 
extrapolated percent of the area under the concentration-time curve from time zero to 
infinity 
AUMC0-inf 
area under the first moment curve extrapolated to infinity 
BID 
twice daily 
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
Cτ 
Plasma concentration at the end of the dosing interval τ (24 hours) on Day 7 and Day 28 
CI 
confidence interval 
CL/F 
apparent total clearance 
CLR 
renal clearance 
Cmax 
maximum plasma concentration 
CPK 
creatine phosphokinase 
CRU 
clinical research unit 
CSR 
clinical study report 
Cτ 
plasma concentration at the end of the dosing interval τ (24 hours) 
CV 
coefficient of variation 
CYP3A 
cytochrome P450 3A 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
Feu 
fraction of dose excreted in urine 
Feu0-τ 
fraction of dose excreted in urine over the dosing interval τ 
Feux-y 
fraction of dose excreted in urine from x to y hours 
FSH 
follicle-stimulating hormone 
GI 
gastrointestinal 
HIV 
human immunodeficiency virus 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
MAD 
multiple ascending dose(ing) 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MDZ 
midazolam 


Shionogi, Inc. 
 
       Final Statistical Analysis Plan, Version 4.0 
 
Protocol: 1908T0911 
 
Date Issued: 10AUG2020 
 
  
 
 
 
VI
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
mean residence time 
PGx 
pharmacogenomic(s) 
PK 
pharmacokinetic(s) 
 
 
PT 
preferred term 
PR 
measure between beginning of P wave until beginning of QRS complex 
QD 
once daily 
QRS 
combination of the Q, R, and S waves 
QT 
QT interval (measure between Q and T wave in heart’s electrical cycle) 
QTc 
corrected QT 
QTcI 
QTc individual 
QTcF 
Fridericia’s corrected QT 
R2 
coefficient of determination 
RBC 
red blood cell  
SAD 
single ascending dose(ing) 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
system organ class 
t1/2,z 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution in the terminal elimination phase 
WBC 
white blood cell 
WHO 
World Health Organization  
λz 
terminal elimination rate constant 
Δ 
change from baseline 
ΔΔ 
placebo-corrected change from baseline 
 
 


Shionogi, Inc. 
 
Final Statistical Analysis Plan, Version 4.0 
Protocol: 1908T0911 
 
Date Issued: 10AUG2020  
 
 
 
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1. Introduction 
 
This document outlines the statistical methods to be implemented during the analysis of 
data collected within the scope of Shionogi, Inc., protocol 1908T0911 (A Phase 1, 
Randomized, Double-Blind, Single-Ascending-Dose, and Food Effect Study to Assess the 
Safety, Tolerability, Ventricular Repolarization, and Pharmacokinetics of S-648414 in 
Healthy Adult Study Participants [Part 1]; A Phase 1, Randomized, Double-Blind, 
Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics 
of S-648414 and A Drug-Drug Interaction Study with the CYP3A Substrate, Midazolam 
(MDZ), in Healthy Adult Study Participants [Part 2]; and A Phase 1 Open-Label Study to 
Assess the Effect of S-648414 on the Pharmacokinetics (PK) of Dolutegravir and the 
Effect of Dolutegravir on the Pharmacokinetics of S-648414 in Healthy Adult Study 
Participants [Part 3]), Amendment 6, dated 17 Jun 2020. The purpose of this statistical 
analysis plan is to define the planned statistical analysis of the study data consistent with 
the study objectives. 
 
S-648414 is a novel antiretroviral agent that is being developed as a treatment for human 
immunodeficiency virus (HIV-1) infection in combination with other antiretroviral agents 
to fully suppress HIV-1 viremia. Based on a full pre-clinical development program of 
S-648414, this study is expected to be conducted safely and the minimum and maximum 
doses tested have been determined based on in-vitro efficacy estimations and animal Good 
Laboratory Practice compliant toxicology studies. These Phase 1 assessments will describe 
the safety, tolerability, and PK of S-648414 following first-in-human dosing, both single 
ascending and multiple ascending dosing (SAD/MAD), food effect, effect on 
electrocardiogram (ECG) parameters, and effect on the PK of MDZ, a cytochrome 
P450 3A (CYP3A) probe, as well as the effect of S-648414 on the PK of dolutegravir and 
the effect of dolutegravir on the PK of S-648414. The study will permit evaluation of 
dosing and safety in the clinical setting to inform and facilitate studies in individuals living 
with HIV-1 infection. 
 
2. Objectives 
 
2.1. Part 1 Objectives 
 
The primary objective is  
• To evaluate the safety and tolerability of S-648414 after administration of a 
single oral dose of S-648414 in healthy adult study participants.  
 
The secondary objectives are 
• To assess the PK of S-648414 after administration of a single oral dose of 
S-648414 in healthy adult study participants 
• To assess the effect of a high-fat meal on the PK of S-648414 after 
administration of a single oral dose of S-648414 in healthy adult study 
participants 


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• To assess the effect of S-648414 on ECG parameters in healthy adult study 
participants 
 
2.2. Part 2 Objectives 
 
The primary objective is  
• To evaluate the safety and tolerability of S-648414 after administration of 
multiple oral doses of S-648414 in healthy adult study participants 
 
The secondary objectives are 
• To assess the PK of S-648414 after administration of multiple oral doses of 
S-648414 in healthy adult study participants 
• To evaluate the potential of S-648414 for inhibition or induction of the CYP3A 
enzymes using MDZ as a probe substrate after administration of multiple oral 
doses of S-648414 in healthy adult study participants 
 
2.3. Part 3 Objectives 
 
The primary objective is  
• To evaluate the effect of S-648414 on the PK of dolutegravir in healthy adult 
study participants   
• To evaluate the effect of dolutegravir on the PK of S648414 in healthy adult 
study participants 
• To evaluate the safety and tolerability of S-648414 after administration of 
multiple oral doses of S-648414 in healthy adult study participants. 
 
The secondary objectives are 
• To evaluate the safety and tolerability after coadministration of dolutegravir 
with S-648414 in healthy adult study participants 
 
3. Investigational Plan 
 
3.1. Overall Study Design and Plan 
 
The study is a randomized, double-blind (Parts 1 and 2) and open-label (Part 3), placebo-
controlled, sequential group study in healthy adult study participants.  
The study consists of Part 1 (SAD, food effect, and effects on ECG parameters including 
concentration-QTc analysis), Part 2 (MAD and drug-drug interaction with the CYP3A 
substrate), and Part 3 (the effect of S-648414 on the PK of dolutegravir and the effect of 
dolutegravir on the PK of S-648414). The sequence of steps in Parts 1, 2, and 3 are 
summarized in Table 12.2.  


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Protocol: 1908T0911 
 
Date Issued: 10AUG2020  
 
 
 
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3.1.1. Part 1 Overall Study Design and Plan 
 
The study consists of a Screening period (Days −28 to −2), admission to the clinical 
research unit (CRU, Day −1), single administrations of S-648414 or matching placebo 
(Day 1), discharge from the CRU (Day 5), and a Follow-up visit (Day 10 ± 2). 
 
In Groups A, B, D, E, and F, eligible healthy adult study participants will be assigned to 1 
of 5 ascending dose groups (10 to 1000 mg) and receive a single oral dose of S-648414 or 
placebo in a fasted state with 6 study participants per dose group receiving active drug and 
2 study participants per dose group receiving placebo. Administration initiates from the 
lowest dose group, and the next group does not initiate until the Follow-up period has been 
completed for the previous group except for A-2 (see Table 3.1.1.1). 
 
In Group C, 8 study participants will be assigned to S-648414, and 2 study participants will 
be assigned to placebo. Study participants assigned to the 100-mg group will receive a 
single oral dose of S-648414 in a fasted state (Group C-1), followed by a single dose of 
S-648414 in a fed state (high-fat meal) (Group C-2). Each episode of dosing will be 
separated by a washout period of at least 14 days. 
 
Table 3.1.1.1 Part 1 Dose Groups 
 
Group Label 
S-648414 Dose 
Number of Active 
Study Participants 
Number of Placebo 
Study Participants 
Group A  
(Group A-1 and A-2)a 
10 mg 
6 
2 
Group B 
30 mg 
6 
2 
Group C  
(Group C-1 and C-2) 
100 mg 
8 
2 
Group D 
250 mg 
6 
2 
Group E 
500 mg 
6 
2 
Group F 
1000 mg 
6 
2 
a 
Because this is a first-in-human administration, the initial dose group (Group A) is divided into 
Group A-1 including 2 study participants (1 S-648414 and 1 placebo) and Group A-2 including 
6 study participants (5 S-648414 and 1 placebo). Study participants in Group A-2 will receive study 
intervention (S-648414 or placebo) in a sentinel dosing sequence, ie, only after confirmation that 
there are no clinical concerns in Group A-1 within 24 hours postdose. 
 
The doses may be changed depending on the results of the safety, tolerability, and PK in 
the preceding group(s), if necessary. The highest dose will not exceed 1000 mg. 
 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group. 
 
The next dose group will not be conducted if any of the following criteria are met: 


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Date Issued: 10AUG2020  
 
 
 
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● Any study participant experiences a treatment-related SAE (ie, treatment-emergent 
SAE [serious adverse event] considered related to the study intervention [S-648414 
or placebo] by the investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related adverse 
events (AEs) 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
See Protocol Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of 
intensity (including HIV grading system), assessment of causality, and procedures for 
recording, evaluating, follow-up, and reporting. 
 
The overall schedule of events for Part 1 is provided in Table 12.1.1. 
 
3.1.2. Part 2 Overall Study Design and Plan 
 
Eligible healthy adult study participants are assigned to 1 of 2 dose groups (50 mg in 
Group G or 30 mg in Group H) and receive multiple oral doses of S-648414 tablet or 
placebo in a fed state with 8 study participants receiving active drug and 2 study 
participants receiving placebo per group (see Table 3.1.2.1). Administration of the next 
dose group (Group H) will not initiate until the Follow-up period has been completed for 
the previous group (Group G).   
In Groups G and H, the study consists of a Screening period (Days −28 to −4), admission 
to the CRU (Day −3), administration of MDZ 5 mg (Day −2 and Day 14) and multiple 
administrations of S-648414 or matching placebo (Days 1 to 14), discharge from the CRU 
(Day 19), and a Follow-up visit (Day 25 ± 2) (see Table 12.1.2).  
All study participants will receive a single oral dose of midazolam 5 mg alone on Day -2 
and coadministered with the S-648414/placebo dose on Day 14. Study participants will 
receive S-648414/placebo once daily (QD) on Days 1 to 14 (Group G will receive 50 mg 
and Group H will receive 30 mg).   
Table 3.1.2.1 Part 2 Dose Groups 
Group Label 
S-648414 Dose 
Number of Active 
Study Participants 
Number of 
Placebo Study 
Participants 
Length of 
Treatment (Days) 
Group G 
50 mg 
8 
2 
14 
Group H 
30 mg 
8 
2 
14 
 
The doses, mode of administration, frequency (ie, QD or twice daily [BID]), dietary 
condition (ie, fasted or fed), or length of administration may be changed depending on the 
results of the safety, tolerability, and PK in the preceding group(s), if necessary. 
 
The investigator and the sponsor will evaluate the results of the safety and tolerability in 
the preceding group(s) and decide whether to proceed to the next dose group.  


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The next dose group will not be conducted if any of the following criteria are met: 
● Any study participant experiences a treatment-related SAE (ie, treatment-emergent 
SAE considered related to the study intervention [S-648414 or placebo] by the 
investigator and sponsor) 
● ≥ 50% of study participants experience grade 2 to 4 treatment-related AEs 
● ≥ 25% of study participants experience grade 3 or 4 treatment-related AEs 
See Protocol Section 10.3 (Appendix 3) for definitions of AEs, SAEs, assessment of 
intensity (including HIV grading system), assessment of causality, and procedures for 
recording, evaluating, and follow-up of AEs and SAEs, and reporting SAEs. 
 
The overall schedule of events for Part 2 is provided in Table 12.1.2. 
 
3.1.3. Part 3 Overall Study Design and Plan 
 
Part 3 is an open-label, non-randomized, 1-sequence, 3-period study.   
 
A total of 14 healthy adult study participants will be enrolled in Group I of Part 3; an 
additional 14 healthy adult study participants will be enrolled in Group J of Part 3.  
 
Part 3 will consist of:   
● Screening period (Days −28 to −2)  
● Period 1 (admission to CRU on Day -1 with continued confinement until Day 8)  
● Mandatory 7-day washout between the last dose of study intervention in Period 1 
and the first dose of study intervention in Period 2  
o Day 8 of Period 1 (no dose)  
o Days 9 to 13 (5-days, no dose)  
The 5-day period can be inpatient or outpatient and will be decided at the 
discretion of the investigator. 
o Day 14 of Period 2 (no dose)  
● Period 2 (confinement: Days 14 to 21)   
● Period 3 (confinement: Days 22 to 29)  
● Follow-up visit (7 days after discharge from the CRU of Period 3 [Day 36] ± 2 
days)  
 
Study participants will receive:   
● Dolutegravir (50 mg orally QD for 7 days) in the fed state during Period 1   
● S-648414 alone (100 mg orally QD for 7 days in Group I or 200 mg orally QD for 
7 days in Group J) in the fed state during Period 2  


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● S-648414 (100 mg orally QD for 7 days in Group I or 200 mg orally QD for 7 days 
in Group J) coadministered with dolutegravir (50 mg orally QD for 7 days) in the 
fed state during Period 3  
See Table 3.1.3.1 for the study schematic.  
 
Table 3.1.3.1 Part 3 Treatment Schedule 
Group 
Label  
Number of  
Study  
Participants  
Period 1a  
Period 2a  
Period 3  
Group I  
14  
Dolutegravir 50 
mg QD for 7 days  
S-648414 100 mg 
QD for 7 days  
S-648414 100 mg + dolutegravir 
50 mg QD for 7 days  
Group J  
14  
Dolutegravir 50 
mg QD for 7 days  
S-648414 200 mg 
QD for 7 days  
S-648414 200 mg + dolutegravir 
50 mg QD for 7 days  
QD = once daily  
a  
There will be a 7-day washout period (of which 5 days are out patient) between Periods 1 and 2; the 
7-day washout period includes the time when the study participant will not receive study intervention on 
the last day of Period 1 and the first day of Period 2.  
The doses, mode of administration, frequency (ie, QD or BID), dietary condition (ie, fasted 
or fed), or length of administration may be changed, if necessary, by the sponsor 
depending on the results of the safety, tolerability, and PK in the preceding group(s).  
 
The overall schedule of events for Part 3 is provided in Table 12.1.3.1 and Table 12.1.3.2. 
 
3.2. Study Endpoints 
3.2.1. Part 1 Study Endpoints 
 
The primary endpoint for Part 1 is: 
• The number and percentage of clinical and laboratory AEs in study 
participants exposed to single dose of S-648414 
 
The secondary endpoints for Part 1 are: 
• S-648414: Cmax, Tmax, AUC, t1/2,z, λz, MRT, CL/F, Vz/F, CLR, and Feu 
following single oral dosing, in fasted and fed state 
• Change from baseline in HR, QTcF, PR and QRS (∆HR, ΔQTcF, ∆PR and 
∆QRS)   
• Placebo-corrected ∆HR, ∆QTcF, ∆PR and ∆QRS (∆∆HR, ∆∆QTcF, ∆∆PR 
and ∆∆QRS)   
• Categorical outliers for HR, QTcF, PR, QRS   
• Frequency of treatment-emergent changes for T-wave morphology and U-
wave presence 
 


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3.2.2. Part 2 Study Endpoints 
 
The primary endpoint for Part 2 is: 
• The number and percentage of clinical and laboratory AEs in study 
participants exposed to multiple doses of S-648414 
 
The secondary endpoints for Part 2 are: 
• S-648414: Cmax, Tmax, AUC, t1/2,z, λz, MRT, CL/F, Vz/F, CLR, and Feu  
• MDZ: Cmax, Tmax, AUC, t1/2,z, λz, and MRT 
 
3.2.3. Part 3 Study Endpoints 
 
The primary endpoint for Part3 is: 
• The number and percentage of clinical and laboratory adverse events in 
study participants exposed to multiple doses of S-648414 
• S-648414 and dolutegravir: Cmax, Tmax, Cτ, AUC, and CL/F 
 
The secondary endpoint for Part 3 is: 
• The number and percentage of clinical and laboratory AEs in study 
participants exposed to multiple doses of S-648414 and dolutegravir 
 
4. General Statistical Considerations 
 
All statistical analyses will be conducted using statistical analysis system SAS® Version 
9.4 or higher (SAS Institute, Cary, NC). For tables and data listings with no data, all titles, 
footnotes and column headers will be presented, and “No data to display” will be 
presented. All tables and data listings will appear in landscape format employing Courier 
New 9-point black font. 
 
Unless otherwise noted, continuous variables will be summarized by using the number of 
nonmissing observations, arithmetic mean, standard deviation (SD), median, minimum, 
and maximum values as descriptive statistics; categorical variables will be summarized by 
using the frequency count and the percentage of study participants in each category as 
descriptive statistics.  
 
Unless otherwise noted, minimum and maximum will be presented to the same number of 
decimal places as the raw data, mean and median will be presented to one more decimal 
place than the raw data, and SD will be presented to one more decimal place than the raw 
data. 
 
Data from subjects excluded from an analysis population will be presented in the data 
listings but not included in the calculation of summary statistics for the corresponding 
analysis population. 
 
All data listings will be sorted by part and subject number. 


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Date Issued: 10AUG2020  
 
 
 
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No algorithm for imputation of missing data will be employed. 
 
For summary of safety assessments, if there are repeated measurements at a time point, the 
original measurement at that time point will be used in the summary tables. If the original 
measurement is missing, the next available measurement at that time point will be used in 
the summary tables.  
 
For Part 1 (other than Group C) and Part 2, baseline will be defined as the last non-missing 
assessment (including repeated and unscheduled assessments) before the first dose of any 
study interventions (S-648414, Midazolam, or Placebo), unless otherwise specified. For 
Part 1 Group C, baseline will be defined as the last non-missing assessment (including 
repeated and unscheduled assessments) before the first dose of any study interventions (S-
648414, Midazolam, or Placebo) for each Period (C1 and C2), unless otherwise specified. 
For Part 3, Baseline will be defined as the last non-missing assessment (including repeated 
and unscheduled assessments) before the first dose of any study interventions 
(Dolutegravir), unless otherwise specified. Unscheduled results will not be included in the 
summary tables except for determining baseline but will be presented in data listings.  
 
For Parts 1 and 2, Study Day will be defined as the day relative to the first exposure of 
either S-648414 or placebo. For Part 3, Study Day will be defined as the day relative to the 
first exposure of Dolutegravir in Period 1. Previous day to Study Day 1 is defined as 
Day -1 (there is no Study Day 0). 
   
In Part 1 and Part 2, all subjects receiving placebo will be pooled across groups for the 
summaries. 
 
4.1. Sample Size 
 
Up to 50 healthy adult study participants in Part 1, 20 healthy adult study participants in 
Part 2, and 28 healthy adult study participants in Part 3 will be enrolled. 
 
No formal calculations were performed to determine sample size for this study. 
 
4.2. Randomization, Stratification, and Blinding 
 
For Part 1 and Part 2, 
 will generate the randomization schedule. Eligible subjects 
within each group will be randomly assigned after all entry criteria have been satisfied 
before the first dose of study intervention administration. Each group will be independently 
randomly assigned by a qualified person who is not directly involved in study conduct, 
data management, or data analysis.  
 
Part 1 and Part 2 are double-blind study. Neither the subjects nor the Investigator will be 
aware of the treatment assignment. Blinding will be maintained throughout the study by 
use of active and placebo dosage forms of similar appearance. Access to the randomization 
code will be strictly controlled according to the standard operating procedures of 
. 


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Date Issued: 10AUG2020  
 
 
 
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 will provide the pharmacy with the randomization schedules for the study and with 
subject-specific blind breaking documents for use in the case of the need for emergency 
unblinding. In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a study participant’s treatment assignment is warranted. Study 
participant safety must always be the first consideration in making such a determination. If 
the investigator decides that unblinding is warranted, the investigator should make every 
effort to contact the sponsor prior to unblinding a study participant’s treatment assignment 
unless this could delay emergency treatment of the study participant. Once it is determined 
to unblind, the investigator should contact the site pharmacist who can break the blind. If a 
study participant’s treatment assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and electronic case report forms (eCRF) as 
applicable. 
 
Stratification will not be used in this study. 
 
Part 3 is open-label, non-randomized. 
 
4.3. Analysis Populations 
 
The enrolled population will include all participants who sign the informed consent (ICF) 
for Part 1 and Part 2, and all participants who sign the ICF and passed screening for Part 3.  
 
The randomized population will include all participants randomly assigned to study 
intervention for Part 1 and Part 2. Participants will be analyzed according to the 
intervention they planned to be received. 
 
The safety population will include all participants who are randomly assigned to study 
intervention, and take at least 1 dose of study intervention for Part 1, Part 2, and all 
participants who take at least 1 dose of study intervention for Part 3. Participants will be 
analyzed according to the intervention they actually received. 
 
The PK concentration population includes all study participants who receive at least 1 dose 
of S-648414 or dolutegravir and have at least 1 evaluable concentration in plasma or urine. 
This population will be used for the concentration listing and plotting of the individual 
concentration-time data. 
 
The PK parameter population includes all study participants with at least 1 PK parameter 
estimated appropriately. This population will be used for PK parameter listing and 
summary and plotting of PK parameter versus dose data. This population will also be used 
for plotting of the mean concentration-time data, the concentration summary and statistical 
analysis. 
 
5. Subject Disposition 
 


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Date Issued: 10AUG2020  
 
 
 
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5.1. Subject Disposition 
 
The number of screen failures and reasons of screen failures will be summarized. Among 
the study participants enrolled into the study, the number and percentage who complete the 
study and who prematurely discontinued the study will be summarized. In addition, 
reasons leading to study discontinuation will be summarized. The number of study 
participants included in each analysis population will also be presented. In addition, the 
number of study participants excluded from each analysis population with those reasons 
will be summarized. 
 
Subject disposition data, screen failure, analysis populations, and randomization data will 
be presented in data listings. 
 
5.2. Protocol Deviations 
 
Significant protocol deviations will be summarized by treatment group and overall. 
Participants could have more than one significant protocol deviation, but are counted once 
for each level of summarization. Protocol deviations will be presented in a data listing. The 
details of protocol deviation category will be defined in a separate document. 
 
6. Demographics and Baseline Characteristics 
 
6.1. Demographics 
 
Demographic and baseline characteristics will be summarized by treatment group and 
overall for each part with descriptive statistics for the safety population. Descriptive 
statistics will be calculated for the following continuous demographic characteristics: age 
(years), weight (kg), height (cm), and body mass index (BMI, kg/m2). Frequency counts 
will be tabulated for the categorical variables of sex (Female, or Male), race (American 
Indian or Alaska Native, Asian, Black or African American, White, or Other), and 
ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, or Unknown). 
 
Demographic information collected at screening will be summarized and presented in a 
data listing.  
 
6.2. Medical History 
 
The medical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA; version to be delineated in the clinical study report [CSR]) and 
presented in a data listing. 
 
6.3. Inclusion and Exclusion Criteria 
 
All inclusion/exclusion criteria deviations recorded in the electronic case report form 
(eCRF) will be presented in a data listing. 
 


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7. Treatments and Medications 
 
7.1. Prior and Concomitant Medications 
 
7.1.1. Prior Medications 
 
Prior medications will be defined as medications that stopped before the first dose of study 
intervention. Prior therapies for drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary. Study participants who have received prior therapy(ies) will be 
listed for the safety population. 
 
7.1.2. Concomitant Medications 
 
Concomitant medications will be defined as medications that started after the date of the 
first dose of study intervention up to the subject’s last visit, or medications that started 
before the first dose of study intervention and are ongoing after the first dose of study 
intervention. 
 
Concomitant therapies for drugs will be coded using the WHO Drug Dictionary. Study 
participants who received concomitant therapy(ies) will be listed for the safety population. 
 
7.2. Medical or Surgical Treatment Procedures 
 
Medical or surgical treatment procedures will be presented in a data listing. 
 
7.3. Study Intervention Administration 
 
The study intervention exposure will be presented in a data listing.   
 
7.4. Meals 
 
Meal data will be presented in a data listing. 
 
8. Pharmacokinetic Analysis 
 
8.1. Pharmacokinetic Sample Concentrations 
 
Blood and urine samples will be collected and analyzed for S-648414 in plasma and urine 
at the following time points: 
 
Part 1 (S-648414):   
 


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Protocol: 1908T0911 
 
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Sample Type 
Scheduled Time (hours) 
Plasma 
Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. 
Urine 
Predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 
hours postdose 
 
Part 2 (S-648414): 
 
Sample 
Type 
Dosing Day 
 
Scheduled Time (hours) 
Plasma 
1 
Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 
hours postdose  
Plasma 
5, 7, 10, 12, 13 
Predose   
Plasma 
14 
Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 
72, and 96 hours postdose 
Urine 
14 
0-24 hours postdose 
 
For Part 2, blood samples will be collected and analyzed for MDZ in plasma at the 
following time points: 
 
Part 2 (MDZ): 
 
Sample 
Type 
Dosing Day 
 
Scheduled Time (hours) 
Plasma 
-2 
Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 
hours postdose. 
Plasma 
14 
Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 
hours postdose. 
 
For Part 3, blood samples will be collected and analyzed for S-648414 in plasma at the 
following time points: 
 
Part 3 (S-648414): 
 


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Protocol: 1908T0911 
 
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Sample 
Type 
Dosing Day 
 
Scheduled Time (hours) 
Plasma 
15, 18, 19, 20 
Predose 
Plasma 
21 
Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours 
postdose. 
Plasma 
22, 25, 26, 27 
Predose 
Plasma 
28 
Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 
hours postdose. 
 
For Part 3, blood samples will be collected and analyzed for dolutegravir in plasma at the 
following time points: 
 
Part 3 (Dolutegravir): 
 
Sample 
Type 
Dosing Day 
 
Scheduled Time (hours) 
Plasma 
1, 4, 5, 6 
Predose 
Plasma 
7 
Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 
24 hours postdose. 
Plasma 
22, 25, 26, 27 
Predose 
Plasma 
28 
Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 
hours postdose. 
 
For each part, plasma concentrations of S-648414, MDZ (Part 2 only) and dolutegravir 
(Part 3 only) will be listed for each subject and time point and summarized by dosing 
regimen with number of subjects in a given dose cohort (N), the number of nonmissing 
observations (n), arithmetic mean (mean), SD, coefficient of variation (CV%, calculated by 
SD/mean × 100), geometric mean, coefficient of variation for geometric mean (geometric 
CV%), median, minimum, and maximum values at each nominal sampling time. The 
geometric CV% will be calculated according to a formula: geometric CV% = [exp (SD2)-
1]1/2 × 100, where SD is for natural log (ln)-transformed data.  
 
For each part, mean plasma concentration versus nominal time profiles will be presented 
for each dosing regimen on both linear and semi-logarithmic scales. Individual plasma 
concentration versus actual time profiles will be grouped by dosing regimen and presented 
on both linear and semi-logarithmic scales. 
 
In Part 2, achievement of steady state for plasma S-648414 concentration will be assessed 
by visual inspection of trough concentration data. 
 


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In Part 3, achievement of steady state for plasma S-648414 and dolutegravir concentrations 
will be assessed by visual inspection of trough concentration data. 
 
For summary of plasma concentration, plasma concentration below the lower limit of 
quantification (BLQ) will be treated as zero (0) for calculations of mean, SD, CV%, 
median, minimum, and maximum values and treated as missing for calculation of 
geometric mean and geometric CV% values. 
 
For each part, urine volume and urine concentration data for S-648414 will be listed by 
subject and collection interval. In Part 1, time course profiles for cumulative fraction of 
dose excreted in urine will be presented graphically. 
 
Descriptive statistics will be presented as follows: 
• 
N and n: no decimal place 
• 
Arithmetic mean, geometric mean, SD, median, Min, and Max: same precision as per 
the observed values 
• 
CV% and Geometric CV%: one decimal place 
 
8.2. Pharmacokinetic Parameters 
 
Pharmacokinetic parameters will be calculated whenever possible for S-648414, MDZ and 
dolutegravir from plasma concentration data by noncompartmental methods using 
Phoenix® WinNonlin® Version 8.0 or higher (Certara USA, Inc., Princeton, NJ). 
Parameters of S- 648414 from urine volume and concentration data will be calculated with 
SAS Version 9.4 or higher. Other parameters may be computed, as appropriate, upon 
review of the data. The estimated PK parameters will be computed for each study 
participant using the actual sample collection times recorded during the study. 
 
Pharmacokinetic parameters (S-648414) for Part 1: 
PK Parameter 
Definition 
Plasma 
Cmax (ng/mL) 
Maximum plasma concentration 
Tmax (hr) 
Time to maximum plasma concentration 
AUC0-last (ng·hr/mL)  
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration after dosing, calculated by linear trapezoidal method when concentrations are 
increasing and by logarithmic trapezoidal method when concentrations are decreasing (Linear 
Up/Log Down Trapezoidal Method) 
AUC0-inf (ng·hr/mL)  
Area under the concentration-time curve extrapolated from time zero to infinity defined as 
AUC0-last + (Clast/λz), where Clast is the last measurable plasma concentration and λz is the 
plasma terminal elimination rate constant 


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AUCextr (%) 
Extrapolated percent of AUC0-inf, calculated as AUCextr (%) = 100 × (AUC0-inf − AUC0-
last)/AUC0-inf 
t1/2,z (hr) 
Terminal elimination half-life, where t1/2,z = (ln2)/λz 
λz (hr-1) 
Terminal elimination rate constant, where λz is the magnitude of the slope of the linear 
regression of the log concentration versus time profile during the terminal phase 
MRT (hr) 
Mean residence time, where MRT = AUMC0-inf/AUC0-inf and AUMC0-inf is the area under the 
first moment curve extrapolated to infinity 
CL/F (L/hr) 
Apparent total clearance estimated according to: CL/F = Dose/AUC0-inf for treatment groups 
Vz/F (L) 
Apparent volume of distribution in the terminal elimination phase, estimated according to: Vz 
/F = Dose/AUC0-inf/λz 
Urine 
Aeux-y (mg) 
Amount of the drug excreted in urine during a given collection time interval from x to y 
hours (Aeu0-24, Aeu24-48, Aeu48-72, Aeu72-96, Aeu0-96) 
Feux-y (%) 
Fraction of dose excreted in urine from x to y hours; calculated as Aeux-y/Dose × 100 (Feu0-24, 
Feu24-48, Feu48-72, Feu72-96, Feu0-96) 
CLR (L/hr) 
Renal clearance estimated according to: CLR = Aeu0-96/AUC0-last 


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Pharmacokinetic parameters (S-648414) for Part 2: 
 
PK Parameter 
Definition 
Plasma 
Cmax (ng/mL) 
Maximum plasma concentration on Day 1 and Day 14 
Tmax  (hr) 
Time to maximum plasma concentration on Day 1 and Day 14 
AUC0-τ (ng·hr/mL)  
Area under the concentration-time curve over the dosing interval on Day 1 and Day 14, 
calculated by Linear Up/Log Down Trapezoidal Method 
t1/2,z (hr) 
Terminal elimination half-life, where t1/2,z = (ln2)/λz on Day 14 
λz (hr-1) 
Terminal elimination rate constant, where λz is the magnitude of the slope of the linear 
regression of the log concentration versus time profile during the terminal phase on Day 14 
CL/F (L/hr) 
Apparent total clearance estimated according to: CL/F = Dose/AUC0-τ on Day 14 
Vz/F (L) 
Apparent volume of distribution in the terminal elimination phase on Day 14, estimated 
according to: Vz /F = Dose/AUC0-τ/λz 
Urine 
Aeu0-τ (mg) 
Amount of the drug excreted in urine over the dosing interval τ on Day 14 
Feu0- τ (%) 
Fraction of dose excreted in urine over the dosing interval τ (24 hours) on Day 14; calculated 
as Aeu0-τ/Dose × 100, where Aeu0-τ is the amount of drug excreted in urine over the dosing 
interval τ (24 hours) 
CLR (L/hr) 
Renal clearance on Day 14, calculated as CLR = Aeu0-τ/AUC0-τ, where Aeu0-τ is the amount of 
drug excreted in urine over the dosing interval τ (24 hours) 
 


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Pharmacokinetic parameters for MDZ on Day -2 and Day 14 for Part 2 include: 
 
PK Parameter 
Definition 
Cmax (ng/mL) 
Maximum plasma concentration 
Tmax (hr) 
Time to maximum plasma concentration 
AUC0-last (ng·hr/mL)  
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration after dosing, calculated by Linear Up/Log Down Trapezoidal Method 
AUC0-inf (ng·hr/mL)  
Area under the concentration-time curve extrapolated from time zero to infinity defined as 
AUC0-last + (Clast/λz), where Clast is the last measurable plasma concentration and λz is the 
plasma terminal elimination rate constant 
AUCextr (%) 
Extrapolated percent of AUC0-inf, calculated as AUCextr (%) = 100 × (AUC0-inf − AUC0-
last)/AUC0-inf 
t1/2,z (hr) 
Terminal elimination half-life, where t1/2,z = (ln2)/λz 
λz (hr-1) 
Terminal elimination rate constant, where λz is the magnitude of the slope of the linear 
regression of the log concentration versus time profile during the terminal phase 
MRT (hr) 
Mean residence time, where MRT = AUMC0-inf/AUC0-inf and AUMC0-inf is the area under the 
first moment curve extrapolated to infinity 
 
Pharmacokinetic parameters for S-648414 in Part 3 on Day 15 and Day 28 include: 
 
PK Parameter 
Definition 
Cmax (ng/mL) 
Maximum plasma concentration 
Tmax (hr) 
Time to maximum plasma concentration 
Cτ 
Plasma concentration at the end of the dosing interval τ (24 hours) 
AUC0-τ (ng·hr/mL)  
Area under the concentration-time curve over the dosing interval τ (24 hours), calculated by 
Linear Up/Log Down Trapezoidal Method 
CL/F (L/hr) 
Apparent total clearance calculated as CL/F =Dose/AUC0-τ 
 
Pharmacokinetic parameters for dolutegravir in Part 3 on Day 7 and Day 28 include: 
 
PK Parameter 
Definition 
Cmax (ng/mL) 
Maximum plasma concentration 
Tmax (hr) 
Time to maximum plasma concentration 
Cτ 
Plasma concentration at the end of the dosing interval τ (24 hours) 
AUC0-τ (ng·hr/mL)  
Area under the concentration-time curve over the dosing interval τ (24 hours), calculated by 
Linear Up/Log Down Trapezoidal Method 
CL/F (L/hr) 
Apparent total clearance calculated as CL/F =Dose/AUC0-τ 
 


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For each part, the estimated PK parameters will be summarized by analyte and dosing 
regimen with N, n, mean, SD, CV%, geometric mean, geometric CV%, median, minimum, 
and maximum values. The Tmax will be summarized by analyte and dosing regimen with N, 
mean, SD, CV%, median, minimum, and maximum values. If the number of PK parameter 
data is < 3, the data will not be summarized. 
 
AUC0-τ will be calculated with observed plasma concentrations from time zero to τ (actual 
time) without extrapolation or interpolation. The actual time for the predose (0 hours) will 
be replaced with zero. If observed plasma concentration at τ is BLQ, AUC0-last will be used 
as AUC0-τ. 
 
If the number of data points used to calculate λz (N_λz) is < 3 (not including Cmax) or the 
calculated coefficient of determination (R2) value for λz is < 0.800, then that study 
participant’s λz, and AUC0-inf, t1/2,z, MRT, CL/F (Day 1), and Vz/F (Day 1), which are 
derived from λz, will be flagged in the data listing and excluded from the descriptive and 
statistical analysis. If λz cannot be determined, then AUC0-inf, t1/2,z, MRT, CL/F (Day 1), 
and Vz/F (Day 1) will not be estimated. N_λz, and R2 value for λz and AUCextr will be 
listed.  
 
If the AUCextr is greater than 20%, then AUC0-inf, MRT, CL/F (Day 1), and Vz/F (Day 1), 
which are derived using AUC0-inf, will be flagged in the data listing and excluded from the 
descriptive statistics and statistical analysis. 
 
Individual plasma concentrations, if deemed to be anomalous, may be excluded from the 
analysis at the discretion of the PK study director. Any such exclusion will be clearly 
represented in the study report along with justification for exclusion. 
 
For the calculations of PK parameters, BLQ before the occurrence of the first quantifiable 
concentration will be treated as zero, and BLQ after the first occurrence of the quantifiable 
concentration will be treated as missing. Urine BLQ concentrations will be treated as 0 for 
calculation of Aeu. 
 
Plasma and urine PK parameters will be presented in the listings as follows: 
• 
Cmax: same precision as per the observed values 
• 
Cτ: same precision as per the observed values 
• 
Tmax: two decimal places 
• 
AUC0-last, AUC0-inf, and AUC0-τ: four significant figures 
• 
AUCextr: one decimal place 
• 
λz: four decimal places 
• 
N_λz:  no decimal place 
• 
R2 value: three decimal places 
• 
MRT, t1/2,z, CL/F, Vz/F, Aeux-y, Feux-y, and CLR: three significant figures 
 
Descriptive statistics will be presented as follows:  
• 
N and n: no decimal place 


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• 
Arithmetic mean, geometric mean, SD, median, Min, and Max: same precision as per 
each PK parameter in the listing. 
• 
CV% and Geometric CV%: one decimal place 
 
8.3. Dose Proportionality Assessments 
 
The dose proportionality of plasma PK parameters of S-648414 will be examined in Part 1 
(all fasted groups), and in Part 2. In Part 1, dose proportionality will be assessed for plasma 
S-648414 Cmax, AUC0-last, and AUC0-inf using power model. The power model assumes a 
linear relationship between the ln-transformed parameter and ln-transformed dose. 
 
 
ln (Parameter) = α + β × ln (Dose) + Random error 
Where Parameter is a given PK parameter, α is the intercept, β is the slope, and Random 
error is a random residual error. Dose proportionality implies that slope = 1 and will be 
assessed by estimating mean slope with the corresponding 95% CI using SAS Proc Reg 
from the power model. 
 
Statistic values of PK parameters will be presented as follows:  
• 
Intercept, slope, standard error, and 95%CIs: three significant figures 
 
In the case where the 95% CI of the slope from the power model does not include 1, the 
differences in ln-transformed Cmax, AUC0-last, and AUC0-inf of S-648414 will be examined 
between treatment groups. An analysis of variance (ANOVA) will be performed using 
SAS Proc Mixed. An ANOVA will also be performed for Part 2. The point estimates and 
90% CIs will be generated for the ratios of all treatment group combinations for ln-
transformed Cmax and AUC (AUC0-last and AUC0-inf for Part 1 and AUC0-τ for Part 2). The 
point estimates and 90% CIs will be back-transformed to obtain the corresponding 
geometric least squares mean ratios and 90% CIs. The following linear model will be used: 
 
ln (Parameter) = Treatment group + Random error 
Where Parameter is a given PK parameter, Treatment group is a fixed treatment group 
effect and Random error is a random residual error.  
The relationship of Cmax, AUC0-last, and AUC0-inf to dose will be graphically presented. 
Dose proportionality will be concluded based on the point estimates and CIs of the power 
model or the ANOVA model and visual inspection of the corresponding plots. 
 
Statistic values of PK parameters will be presented as follows:  
• 
Geometric least squares (LS) means: same precision as geometric mean in Section 8.2 
• 
Mean ratios and 90% CIs: four significant figures 
 


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8.4. Dose Independency Assessments 
 
Dose independence of plasma PK parameters of S-648414 will be examined between the 
treatment groups in Part 1 (all fasted groups) and Part 2. For S-648414 t1/2,z, CL/F, Vz/F, 
MRT, and CLR, the difference between treatment groups will be examined for dose 
independence using the ANOVA model. An ANOVA will be performed using SAS Proc 
Mixed. The point estimates and 90% CIs will be generated for all treatment group 
combinations for ln-transformed t1/2,z, CL/F, Vz/F, MRT, and CLR. The point estimates and 
90% CIs will be back-transformed to obtain the corresponding geometric least squares 
mean ratios and 90% CIs. The following linear model will be used: 
 
ln (Parameter) = Treatment group + Random error 
 
Where Parameter is a given PK parameter, Treatment group is a fixed treatment group 
effect and Random error is a random residual error. 
 
The relationship of t1/2,z, CL/F, Vz/F, MRT, and CLR for plasma S-648414 to S-648414 
dose will be presented graphically. 
 
Dose independency will be concluded based on the point estimates and 90% CIs of the 
ANOVA model and visual inspection of the corresponding plots. 
 
Statistic values of PK parameters will be presented as follows:  
• 
Geometric LS means: same precision as geometric mean in Section 8.2 
• 
Mean ratios and 90% CIs: four decimal places 
 
8.5. Food Effect Assessment 
 
S-648414 plasma PK data following a single administration of S-648414 tablet will be 
compared between fasted and fed conditions. An ANOVA will be performed using SAS 
Proc Mixed for ln-transformed Cmax, AUC0-last, AUC0-inf, and t1/2,z for plasma S-648414. 
 
In case of unbalanced data, the Kenward-Roger method will be used to compute the 
denominator degrees of freedom for the tests of fixed effects in this analysis. The point 
estimates and 90% CIs will be generated for the differences between PK in the fed state 
and PK in the fasted state for ln transformed Cmax, AUC0-last, AUC0-inf, and t1/2,z. The point 
estimates and 90% CIs will be back-transformed to obtain the corresponding geometric 
least squares mean ratios and 90% CIs as the following ratio. 
 
(PK in the fed state) / (PK in the fasted state)  
 
The following linear mixed effects model will be used: 
ln (Parameter) = Food condition + Subject + Random error 
 
Where Food condition is a fixed effect of food condition, Subject is a random effect of 
study participant, and Random error is a random residual error. 


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The comparison of Cmax, Tmax, AUC0-last, AUC0-inf, and t1/2,z for plasma S-648414 between 
the fasted state and the fed state will be presented graphically. 
 
The effect of food will be concluded based on the point estimates and 90% CIs of the 
ANOVA model and visual inspection of the corresponding plots. 
 
Statistic values of PK parameters will be presented as follows: 
• 
Geometric LS means: same precision as geometric mean in Section 8.2 
• 
Mean ratios and 90% CIs: four decimal places 
 
8.6. Accumulation Assessment 
 
When data are available, the accumulation ratios of S-648414 calculated as ratios of Day 
14 to Day 1 will be assessed in Part 2. An ANOVA will be performed using SAS Proc 
Mixed for ln-transformed Cmax and AUC0-τ. In case of unbalanced data, the Kenward-
Roger method will be used to compute the denominator degrees of freedom for the tests of 
a fixed effect in the analysis. The point estimates and their 90% CIs will be generated for 
the differences between Days 1 and 14 for ln-transformed Cmax and AUC0-τ in each dose 
group. The point estimates and the 90% CIs will be back-transformed to obtain the 
corresponding geometric least squares mean ratios and the 90% CIs. The following linear 
mixed effects model will be used: 
 
ln (Parameter) = Day + Subject + Random error 
 
Where Day is a fixed effect of day, Subject is a random effect of study participant, and 
Random error is a random residual error. 
 
Statistic values of PK parameters will be presented as follows: 
• 
Geometric LS means: same precision as geometric mean in Section 8.2 
• 
Mean ratios and 90% CIs: four decimal places. 
 
8.7. Effect of S-648414 on the Pharmacokinetics of Midazolam 
 
When data are available, the effect of S-648414 on the plasma PK of MDZ will be 
assessed. An ANOVA will be performed using SAS Proc Mixed for ln-transformed Cmax, 
AUC0-last, and AUC0-inf of MDZ. In case of unbalanced data, the Kenward-Roger method 
will be used to compute the denominator degrees of freedom for the tests of a fixed effect 
in the analysis. The point estimates and their 90% CIs will be generated for the differences 
between MDZ coadministered with S-648414 and MDZ alone for ln-transformed Cmax, 
AUC0-last, and AUC0-inf. The point estimates and their 90% CIs will be back-transformed to 
obtain the corresponding geometric least squares mean ratios and 90% CIs as the following 
ratio: 
(MDZ coadministered with S-648414) / (MDZ alone) 
The following linear mixed effects model will be used: 
 


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ln (Parameter) = Treatment + Subject + Random error 
 
Where Treatment is a fixed effect of treatment, Subject is a random effect of study 
participant, and Random error is a random residual error. 
 
The drug interaction will be assessed by whether the 90% CIs for Cmax, AUC0-last, and 
AUC0-inf of MDZ are completely contained within the range of 0.8000 to 1.2500. The 
comparison of Cmax, Tmax, AUC0-last, and AUC0-inf between MDZ alone and MDZ 
coadministered with S-648414 will be presented graphically. 
 
The effect of S-648414 on the plasma PK of MDZ will be concluded based on the point 
estimates and 90% CIs of the ANOVA model and visual inspection of the corresponding 
plots. 
 
Statistic values of PK parameters will be presented as follows:  
• 
Geometric LS means: same precision as geometric mean in Section 8.2 
• 
Mean ratios and 90% CIs: four decimal places 
 
8.8. Effect of S-648414 on the Pharmacokinetics of Dolutegravir 
 
When data are available, the effect of S-648414 on the plasma PK of dolutegravir will be 
assessed. An ANOVA will be performed using SAS Proc Mixed for ln-transformed Cmax, 
Cτ, and AUC0-τ of dolutegravir. In case of unbalanced data, the Kenward-Roger method 
will be used to compute the denominator degrees of freedom for the tests of a fixed effect 
in the analysis. The point estimates and their 90% CIs will be generated for the differences 
between dolutegravir coadministered with S-648414 and dolutegravir alone for 
ln-transformed Cmax, Cτ, and AUC0-τ. The point estimates and their 90% CIs will be back-
transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs 
as the following ratio: 
(dolutegravir coadministered with S-648414) / (dolutegravir alone) 
The following linear mixed effects model will be used: 
 
ln (Parameter) = Treatment + Subject + Random error 
 
Where Treatment is a fixed effect of treatment, Subject is a random effect of study 
participant, and Random error is a random residual error. 
 
The drug interaction will be assessed by whether the 90% Cmax, Cτ, and AUC0-τ of 
dolutegravir are completely contained within the range of 0.8000 to 1.2500. The 
comparison of Cmax, Cτ, and AUC0-τ between dolutegravir alone and dolutegravir 
coadministered with S-648414 will be presented graphically. 
 
The effect of S-648414 on the plasma PK of dolutegravir will be concluded based on the 
point estimates and 90% CIs of the ANOVA model and visual inspection of the 
corresponding plots. 
 


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Statistic values of PK parameters will be presented as follows:  
• 
Geometric LS means: same precision as geometric mean in Section 8.2 
• 
Mean ratios and 90% CIs: four decimal places 
 
8.9. Effect of Dolutegravir on the Pharmacokinetics of S-648414 
 
When data are available, the effect of dolutegravir on the plasma PK of S-648414 will be 
assessed. An ANOVA will be performed using SAS Proc Mixed for ln-transformed Cmax, 
Cτ, and AUC0-τ of S-648414. In case of unbalanced data, the Kenward-Roger method will 
be used to compute the denominator degrees of freedom for the tests of a fixed effect in the 
analysis. The point estimates and their 90% CIs will be generated for the differences 
between S-648414 coadministered with dolutegravir and S-648414 alone for 
ln-transformed Cmax, Cτ, and AUC0-τ. The point estimates and their 90% CIs will be back-
transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs 
as the following ratio: 
(S-648414 coadministered with dolutegravir) / (S-648414 alone) 
The following linear mixed effects model will be used: 
 
ln (Parameter) = Treatment + Subject + Random error 
 
Where Treatment is a fixed effect of treatment, Subject is a random effect of study 
participant, and Random error is a random residual error. 
 
The drug interaction will be assessed by whether the 90% Cmax, Cτ, and AUC0-τ of 
dolutegravir are completely contained within the range of 0.8000 to 1.2500. The 
comparison of Cmax, Cτ, and AUC0-τ between S-648414  alone and S-648414 
coadministered with dolutegravir will be presented graphically. 
 
The effect of dolutegravir on the plasma PK of S-648414 will be concluded based on the 
point estimates and 90% CIs of the ANOVA model and visual inspection of the 
corresponding plots. 
 
Statistic values of PK parameters will be presented as follows:  
• 
Geometric LS means: same precision as geometric mean in Section 8.2 
• 
Mean ratios and 90% CIs: four decimal places 
 
9. Safety Analysis 
 
9.1. Adverse Events 
 
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, 
disease, or laboratory or physiologic observations occurring in a person given a study 
intervention in a clinical study.  The event does not need to be causally related to the study 
intervention or clinical study.  
 


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A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
any of study interventions ((S-648414, Midazolam, Dolutegravir, or Placebo) or any event 
already present that worsens in intensity or frequency after exposure to study intervention. 
A TEAE will be summarized to a given treatment if the event onset/worsening occurs any 
time after the dose in that period and before the dose in the next period. 
Adverse Events will be coded by system organ class (SOC) and preferred term (PT) 
according to MedDRA, version to be delineated in the CSR. 
 
All summary tables will include number and percentage of subjects and number of events. 
For the number of AEs, each occurrence will be counted once. In the summary tables 
where both SOC and PT are presented, AEs will be sorted in descending order of 
frequency of SOC based on the total of all treatment groups, and then alphabetically. 
Within each SOC, AEs will be sorted in descending order of frequency of preferred terms 
based on the total of all treatment groups, and then alphabetically. A subject with 2 or 
more AEs within the same level of summarization will be counted only once in that level 
using the most extreme incident (for the severity table) or the most related (for the 
relationship to study intervention table). Percentages will be based upon the number of 
subjects in the safety population by treatment group.  
 
9.1.1. Incidence of Adverse Events 
 
An overview of AEs will be presented by treatment group and overall for each part, 
including number and percentage of subjects with any: 
• TEAE 
• Treatment-related TEAE (S-648414 or placebo related, MDZ related, and 
Dolutegravir related) 
• Any TEAE with Severity Grade 2-4 
• Any TEAE with Severity Grade 3-4 
• Gastrointestinal (GI) AE 
• Ocular AE 
• SAE 
• Treatment-related SAE (S-648414 or placebo related, MDZ related,  and 
Dolutegravir related) 
• TEAE leading to study discontinuation 
• TEAE leading to study intervention (S-648414 or placebo related, MDZ related,  
and Dolutegravir related) discontinuation 
• Death 
 
All TEAEs will be presented in a summary table by treatment and total for each SOC and 
PT.  
 
All AEs recorded in the eCRF will be presented in a data listing.  
 


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9.1.2. Relationship of Adverse Events to Study Intervention 
 
The relationship of AE to study intervention (S-648414 or placebo, MDZ, and 
Dolutegravir separately) will be classified as Not Related or Related to each study 
intervention by the Investigator.  
 
Treatment-emergent AEs will be summarized by SOC, PT, and relationship to study 
intervention, and presented by treatment group and overall for each part. If there are any 
missing relationship information, a missing category will be added to the summary table. 
At each level of subject summarization, a subject is classified according to the closest 
relationship if the subject reported one or more events. 
 
S-648414 or placebo related TEAEs, Midazolam related TEAEs, and Dolutegravir related 
TEAEs will be presented in data listings. 
 
9.1.3. Severity of Adverse Event 
 
The severity of AEs will be classified as Mild, Moderate, Severe, and Potentially 
life-threatening by the Investigator.  
 
Treatment-emergent AEs will be summarized by SOC, PT, and severity, and presented by 
treatment group and overall for each part. Moreover, Treatment-related AEs will be 
summarized by SOC, PT, and severity, and presented by treatment group and overall for 
each part in a separate summary table. If there are any missing severity information, a 
Missing category will be added in summary table. At each level of subject summarization, 
a subject is classified according to the highest severity if the subject reported one or more 
events. 
 
9.1.4. Serious Adverse Events 
 
An SAE is an AE that:  
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
• Results in a persistent disability/incapacity 
• Results in a congenital anomaly or birth defect 
 
Additionally, medical or scientific judgment 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 hospitalization but may jeopardize 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. 
 




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Clinical chemistrya 
Blood urea 
nitrogen  
Potassium 
AST  
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT 
Total protein 
Glucose 
fasting 
Calcium 
ALP 
Total cholesterol 
Uric acid 
Chloride 
GGT  
 
CRP 
CPK 
LDH  
 
Routine urinalysisb 
• Specific gravity 
• pH, glucose, protein, blood, ketones, urobilinogen, bilirubin, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other screening tests 
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
nonchildbearing potential only) 
• 
Urine Pregnancy Test (only for females who are not diagnosed as 
postmenopausal.) 
• 
Urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) 
• 
Serology (syphilis, HIV antibody, hepatitis B surface antigen, and 
hepatitis C virus antibody) 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CPK = creatine phosphokinase; CRP = C-reactive protein; GGT = gamma glutamyl transferase; 
HIV = human immunodeficiency virus; INR = international normalized ratio; Institutional Review Board 
(IRB) / Independent Ethics Committee (IEC) = Institutional Review Board/Independent Ethics 
Committee; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCV = mean 
corpuscular volume; RBC = red blood cell; SAE = serious adverse event; ULN = upper limit of normal; 
WBC = white blood cell 
a 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Protocol Section 7.1.1 and Section 10.6 (Appendix 6). All 
events of ALT ≥ 3 × ULN and bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT > 3 × ULN and 
INR > 1.5, if INR measured which may indicate severe liver injury (possible “Hy’s Law”) and must 
be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
b 
Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/IEC. 
All study-required laboratory assessments will be performed by a local laboratory. 
 
Abnormal clinical laboratory values will be flagged as either high or low (or normal or 
abnormal) based on the reference ranges for each laboratory parameter.  The investigator 
will determine whether any of the abnormally high or low results are clinically significant 
or not clinically significant.   
 
Actual results and changes from baseline values for hematology, clinical chemistry, and 
routine urinalysis tests will be summarized by visit and treatment group for each part.  


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Shift from baseline in hematology, clinical chemistry, and routine urinalysis tests results 
relative to the reference range will be summarized by visit and treatment group by each 
part, using the frequency count and percentage of subjects in each category.  
 
All laboratory data will be presented in data listings. 
 
9.3. Vital Sign Measurements 
 
Vital sign measurements will include body temperature, pulse rate, respiratory rate, and 
blood pressure. The average of 3 consecutive readings for blood pressure will be displayed 
in summaries and all of the 3 readings will be displayed in listings. Vital signs will be 
measured at the time points indicated in the schedule of assessments (Section 12.1). 
 
The investigator will determine if any of the vital sign measurements are clinically 
significant or not clinically significant.  
 
Actual results and changes from baseline values for vital sign data will be summarized by 
visit and treatment group for each part. 
 
All vital sign and weight/BMI data will be presented in a data listing. 
 
9.4. Electrocardiogram 
 
A triplicate 12-lead ECG for safety assessment will be obtained as outlined in the schedule 
of assessments (Section 12.1). 
 
The investigator will determine whether any of the 12-lead ECG results are clinically 
significant or not clinically significant. Findings of 12-lead ECG will be classified as either 
“normal”, “abnormal, not clinically significant”, or “abnormal, clinically significant”. 
 
For interpretation of triplicate 12-lead ECGs, baseline will be defined as the best case of 
the last non-missing triplicate measurements (including repeated and unscheduled 
measurements) before the start of first study intervention administration. For calculation of 
post-dose summary statistics, the worst case of the non-missing triplicate measurements 
will be used.  The order of interpretation for 12-lead ECGs (best to worst case): Normal; 
Abnormal, Not Clinically Significant; Abnormal, Clinically Significant.  
 
The shift from baseline of categorical investigator interpretation will be summarized at 
each visit by treatment group for each part for the safety population. 
 
The investigator’s interpretation will be presented in a data listing for the safety 
population. 
 
Cardiodynamic Electrocardiogram evaluations extracted from Holter recording will be in a 
separate SAP by another vendor. 


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9.5. Ophthalmological Examinations 
 
Ophthalmological examinations performed in Parts 1 and 2 will include fundoscopy, 
tonometry (intraocular pressure), and a visual acuity test. Assessments will be carried out 
by an opthalmologist at the specified time points in the schedule of assessments (Section 
12.1). 
 
Ophthalmological examinations results will be presented in a data listing. 
 
9.6. Physical Examination 
 
Complete physical examinations and symptom-focused physical examinations relevant to 
the study participant’s current condition will be performed as clinically indicated at visits 
specified in the schedule of assessments (Section 12.1). 
 
The shift from baseline of categorical interpretation (normal, abnormal – not clinically 
significant, abnormal – clinically significant) will be summarized at each visit by treatment 
group for each part. 
 
Physical examination results will be presented in a data listing. 
 
9.7. Liver Events 
 
When any safety test result meets the management and discontinuation criteria for liver 
function abnormalities (Protocol Section Error! Reference source not found. and 
Protocol Section Error! Reference source not found. [Appendix 6]), the results of further 
assessments and required follow-up should be recorded in the Liver Event Form. 
 
Abnormal Liver Chemistry Criteria will be summarized by treatment group for each part 
for the safety population. Liver Events data will be presented in a data listing. 
 
9.8. Biomarkers Sample Collection 
 
Biomarkers (4β-hydroxycholesterol and cholesterol) in plasma will be measured as an 
enzyme activity marker. Biomarkers will be collected as specified in the Schedule of 
Activities (see Table 3.1.2.1). The study plans and results will be reported separately. 
 
10. Interim Analysis 
 
No interim analyses for efficacy are planned in this study. However, ongoing assessments 
of the safety, tolerability, and PK will occur between the investigator and the sponsor. 
Criteria for determining whether to proceed to next dose group are included in Protocol 
Section 6.6.1 (Part 1) and Section 6.6.2 (Part 2). To assist with the evaluation and dose 
selection for the S-648414 Proof of Concept study, the sponsor will be unblinded after the 


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completion of Part 2 and an evaluation of safety and PK data from Parts 1 and 2 will be 
conducted. 
 
For open-label Part 3, Group J will receive 50 mg of S-648414 and will only be conducted 
if relevant interaction is observed with dolutegravir and S-648414 based on interim review 
of Group I (see Section 6.6.3 for Part 3). 
 
No independent data monitoring committee will be established for this study. 
 
11. Change in Planned Analysis 
 
In Protocol, the enrolled population is defined as all participants who sign the ICF; The 
safety population is defined as all participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  
 
In the SAP for Part 3: the enrolled population will include all participants who sign the ICF 
and passed screening; The safety population will include all participants who take at least 1 
dose of study intervention.






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BMI = body mass index; CRU = clinical research unit; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; PGx = pharmacogenomics; PK = pharmacokinetic 
a 
Study participants will be admitted to the CRU the day prior to the administration of study intervention (S-648414 or placebo) in the morning on Day -1 
and discharged on Day 5 after the completion of all study procedures.  
b 
Medical history includes a review of prior therapies (30 days prior to Screening visit). 
c 
Height will be measured only at Screening. 
d 
Vital signs include oral body temperature, pulse rate (1 measurement), respiratory rate, and blood pressure (3 consecutive readings) collected at 
Screening, Admission Day (Day -1), Day 1: predose (0 hours), 1.5, 3, 5, 8, and 12 hours postdose, Day 2: 24 hours postdose, Day 3: 48 hours postdose, 
Day 4: 72 hours postdose, Day 5: 96 hours postdose, and Follow-up (Days 8 to 12) or Early Termination visit. Allowable time frame for collection is 
± 20 minutes (2 to 0 hours for the predose collection).  
e 
Symptom-focused physical examinations include updates only. 
f 
Electrocardiograms for safety assessment at Screening, Admission Day (Day -1), Day 1: predose (0 hours), 1, 3, 5, and 12 hours postdose, Day 2: 
24 hours postdose, Day 5: 96 hours postdose, and Follow-up (Days 8 to 12) or Early Termination visit. Allowable time frame for collection is 
± 8 minutes (2 to 0 hours for the predose collection). 
g 
Cardiodynamic evaluations include High-precision 12-lead ECG tracings will be extracted from Holter recordings during the following time points: 
Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. For Group C, ECG will not be 
collected in Step 3-2. Electrocardiograms will be recorded after vital signs and prior to blood draws. Study participants will need to rest in the supine 
position for 10 minutes before and during the vital signs, ECGs, and blood draws and the rest must be documented in source notes. Allowable time frame 
for collection is ± 8 minutes (2 to 0 hours for the predose collection). 
h 
Ophthalmological assessments will be carried out by an ophthalmologist at the specified time points. 
i 
Additional data collection required for gastrointestinal adverse events: nausea, vomiting, diarrhea, and abdominal pain. 
j 
Serological tests include testing for positive syphilis, positive hepatitis B surface antigen, positive hepatitis C virus antibody, and positive HIV 
antigen/antibody. 
k 
Urine pregnancy test is only for females who are not diagnosed as postmenopausal. 
l 
Blood sample for serum FSH levels must be obtained to confirm female study participant’s postmenopausal status if there is no available documentation 
confirming postmenopausal status. 
m Laboratory tests include hematology, blood chemistry, and urinalysis. 
n 
Pharmacokinetic blood samples collected at predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose (Day 1), 24 hours postdose (Day 2), 
48 hours postdose (Day 3), 72 hours postdose (Day 4), and 96 hours postdose (Day 5). The PK blood sampling schedule may be changed according to the 
PK results in the preceding group(s). Allowable time frame for collection is ± 5 minutes, with the exception of the samples collected ≥ 24 hours postdose 
which is ± 30 minutes. 
o 
For study participants who agree to participate in the PGx research, these samples should be obtained on Admission Day (Day -1). 
p 
Pharmacokinetic urine samples collected at predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose. The time 
intervals for urine sampling may be changed according to the PK results in the preceding group(s). 
q 
Metabolite profiling collected at predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose (Day 1), 24 hours postdose (Day 2), 48 hours 
postdose (Day 3), 72 hours postdose (Day 4), and 96 hours postdose (Day 5) for plasma samples. Metabolite profiling collected at predose (-12 to 
0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose for urine samples.  


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r 
Study intervention (S-648414 or placebo) will be administered after an overnight fast of at least 10 hours. For group C, the second dose (Step 3-2) will be 
administered 30 minutes after the initiation of breakfast (high-fat meal). 
s 
For Group C, study participants will receive the first dose of study intervention (100 mg) in a fasted state (Group C-1), followed by a ≥ 14 days washout 
period and then the second dose of study intervention (100 mg) in a fed state (Group C-2). 
For the group of study participants who will be assessed for the effect of food (Group C), Step 3-1 and Step 3-2 study procedures will be started on Day -1.  
Unless otherwise stated, predose procedures will be completed within approximately 1 hour of dosing and approximately ± 10 minutes for all postdose 
procedures. 
 
 
 
 






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BMI = body mass index; CRU = clinical research unit; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; PGx = pharmacogenomics; PK = pharmacokinetic 
a 
Study participants will be admitted to the CRU the day prior to the administration of midazolam and discharged on Day 19 after the completion of all 
study procedures. 
b 
Medical history includes a review of prior therapies (30 days prior to Screening visit). 
c 
Height will be measured only at Screening. 
d 
Vital signs include oral body temperature, pulse rate (1 measurement), respiratory rate, and blood pressure (3 consecutive readings) collected at 
Screening, Admission Day (Day -3), Day -2: predose (0 hours) and 1.5 hours postdose, Day -1: Morning, Day 1: predose (0 hours), 0.5, 1.5, 3, 6, 8, and 
12 hours postdose, Day 2 to Day 13: predose (0 hours), Day 14: predose (0 hours), 1.5, 6, and 12 hours postdose, Day 15 to 18: Morning, Day 19: 
120 hours postdose (at discharge), and Follow-up (Day 23 to 27) or Early Termination visit. Allowable time frame for collection is ± 20 minutes (2 to 
0 hours for the predose collection).  
e 
Symptom-focused physical examinations include updates only. 
f 
Electrocardiograms for safety assessment at Screening, Admission Day (Day -3), Day -2: predose (0 hours), 1.5, 6, and 12 hours postdose, Day 1: 
predose (0 hours), 1.5, 6, and 12 hours postdose, Days 2, 5, 8, 11, and 14: predose (0 hours) and 1.5 hours postdose, Day 19:120 hours postdose (at 
discharge), Follow-up (Day 23 to 27) or Early Termination visit. Allowable time frame for collection is ± 8 minutes (2 to 0 hours for the predose 
collection). 
g 
Ophthalmological assessments will be carried out by an ophthalmologist at the specified time points. 
h 
Additional data collection required for gastrointestinal adverse events: nausea, vomiting, diarrhea, and abdominal pain. 
i 
Serological tests include testing for positive syphilis, positive hepatitis B surface antigen, positive hepatitis C virus antibody, and positive HIV 
antigen/antibody. 
j 
Urine pregnancy test is only for females who are not diagnosed as postmenopausal. 
k 
Blood sample for serum FSH levels must be obtained to confirm female study participant’s postmenopausal status if there is no available documentation 
confirming postmenopausal status. 
l 
Laboratory tests include hematology, blood chemistry, and urinalysis.  
m Pharmacokinetic blood samples collected at: 
 
Day -2 (midazolam): predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. 
 
Day 1 (S-648414): predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. 
 
Days 5, 7, 10, 12, and 13 (S-648414): predose (0 hours). 
 
Day 14 (midazolam): predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. 
 
Day 14 (S-648414): predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose. 
 
Allowable time frame for collection is ± 5 minutes and ≥ 24 hours after dosing is ± 30 minutes. 
n 
For study participants who agree to participate in the PGx research only, these samples should be obtained on Admission Day (Day -3). 
o 
Pharmacokinetic urine sample collected on Day 14 only (0 to 24 hours postdose). 
p 
Biomarker sample collected on Day -2 and Day 14 (4 and 24 hours postdose). Allowable time frame for collection is ± 10 minutes, with the exception of 
the samples collected ≥ 24 hours after dosing which is ± 30 minutes. 
q 
The study intervention (S-648414 or placebo) will be administered 30 minutes after the initiation of breakfast. 


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Unless otherwise stated, predose procedures will be completed within approximately 1 hour of dosing and approximately ± 10 minutes for all postdose 
procedures. 
 
 
 












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i 
Additional data collection required for gastrointestinal adverse events: nausea, vomiting, diarrhea, and abdominal pain. 
j 
Urine pregnancy test is only for females who are not diagnosed as postmenopausal. 
k 
Laboratory tests include hematology, blood chemistry, and urinalysis. 
l 
Pharmacokinetic blood samples collected.  
 
In Period 2, S-648414: Day 15: Pre-dose (0 hours), Day 18 to 20: Pre-dose (0 hours), Day 21: Predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours 
postdose. 
 
In Period 3, S-648414 and dolutegravir: Day 22: Pre-dose (24 hours after Day 21 dose), Day 25 to 27: Pre-dose (0 hours), Day 28: Predose (0 hours), 0.5, 1, 
1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose (Day 29). 
 
Allowable time frame for collection is ± 5 minutes and ≥ 24 hours after dosing is ± 30 minutes. 
m Study intervention (S-648414) will be administered during Period 2 and study intervention (S-648414 and dolutegravir) will be administered during Period 3 to 
study participants in a fed state (ie, 30 minutes after initiation of breakfast).  
Unless otherwise stated, predose procedures will be completed within approximately 1 hour of dosing and approximately ± 10 minutes for all postdose procedures. 
 


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12.2. 
Sequence of Steps 
Group 
Sequence 
Part 1 – Single dosing after overnight fast of ≥ 10 hours 
Group A-1a 
(10 mg) 
Step 1-1 
 
 
 
 
 
 
 
 
 
 
Group A-2a 
(10 mg) 
 
Step 1-2 
 
 
 
 
 
 
 
 
 
Group B 
(30 mg) 
 
 
Step 2 
 
 
 
 
 
 
 
 
Group Cb 
(100 mg) 
 
 
 
Step 3-1 
Fasted 
Step 3-2 
Fed (30 minutes after the 
initiation of breakfast) 
 
 
 
 
 
Group D  
(250 mg) 
 
 
 
 
Step 4 
 
 
 
 
 
 
Group E  
(500 mg) 
 
 
 
 
 
Step 5 
 
 
 
 
 
Group F 
(1000 mg) 
 
 
 
 
 
 
Step 6 
 
 
 
 
Part 2 – Multiple dosing administered 30 minutes after the initiation of breakfast 
 
 
Group G  
(50 mg)  
 
 
 
 
 
 
 
Step 7c 
MDZ 
 
 
 
Group H 
(30 mg)  
 
 
 
 
 
 
 
 
Step 8c 
MDZ 
 
 
Part 3 – Multiple dosing administered 30 minutes after the initiation of breakfast 
Group I 
(100 mg) 
 
 
 
 
 
 
 
 
 
Step 9d 
 
Group J 
(200 mg) 
 
 
 
 
 
 
 
 
 
 
Step 10d 


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MDZ = midazolam 
a 
The initial dose group (Group A) is divided into Group A-1 including 2 study participants (1 S-648414 and 1 placebo) and Group A-2 including 6 study 
participants (5 S-648414 and 1 placebo). Study participants in Group A-2 will receive study intervention (S-648414 or placebo) in a sentinel dosing 
sequence, ie, only after confirmation that there are no clinical concerns in Group A-1 within 24 hours postdose.  
b 
Group C-1 is the same as Step 3-1, and will be followed sequentially by Group C-2 (Step 3-2). For Group C, study participants will receive the first dose 
of study intervention (100 mg) in a fasted state (Group C-1), followed by a ≥ 14 days washout period and then the second dose of study intervention 
(100 mg) in a fed state (Group C-2). 
c 
Steps 7 and 8 will include administration of MDZ on Day -2 and Day 14 and multiple administrations of S-648414 or matching placebo. 
d 
Steps 9 and 10 will include administration of dolutegravir 50 mg once daily for 7 days, followed by a washout period of at least 7 days, followed by 
administration of S-648414 for 7 days, followed by coadministration of S-648414 and dolutegravir 50 mg once daily for 7 days.