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Evaluation of Safety, Tolerability, Pharmacokinetics, Drug-Drug and Food Interactions of Single and Multiple Doses of S-648414 in Healthy Adults

Sponsor
Shionogi (Industry)
Overall Status
Completed
CT.gov ID
NCT04147715
Collaborator
(none)
98
Enrollment
2
Locations
12
Arms
11.7
Actual Duration (Months)
49
Patients Per Site
4.2
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

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)"

Study Design

Study Type:
Interventional
Actual Enrollment :
98 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Masking:
Double (Participant, Investigator)
Masking Description:
Parts 1 and 2 were blinded studies. Part 3 was an open-label study and, therefore, did not include blinding.
Primary Purpose:
Treatment
Official 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)
Actual Study Start Date :
Oct 9, 2019
Actual Primary Completion Date :
Sep 22, 2020
Actual Study Completion Date :
Sep 29, 2020

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Part 1: Placebo

Participants received a single oral dose of matching placebo in a fasted state on Day 1.

Drug: Placebo
Tablet for oral administration
Experimental: Part 1: 10 mg S-648414

Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1.

Drug: S-648414
Tablet for oral administration
Experimental: Part 1: 30 mg S-648414

Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1.

Drug: S-648414
Tablet for oral administration
Experimental: Part 1: 100 mg S-648414

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.

Drug: S-648414
Tablet for oral administration
Experimental: Part 1: 250 mg S-648414

Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1.

Drug: S-648414
Tablet for oral administration
Experimental: Part 1: 500 mg S-648414

Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1.

Drug: S-648414
Tablet for oral administration
Experimental: Part 1: 1000 mg S-648414

Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.

Drug: S-648414
Tablet for oral administration
Placebo Comparator: Part 2: Placebo + Midazolam

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.

Drug: Placebo
Tablet for oral administration

Drug: Midazolam
Solution for oral administration
Other Names:
  • Versed

    		•
    Experimental: Part 2: 50 mg S-648414 + Midazolam

    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.

    Drug: S-648414
    Tablet for oral administration

    Drug: Midazolam
    Solution for oral administration
    Other Names:
  • Versed

    		•
    Experimental: Part 2: 30 mg S-648414 + Midazolam

    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.

    Drug: S-648414
    Tablet for oral administration

    Drug: Midazolam
    Solution for oral administration
    Other Names:
  • Versed

    		•
    Experimental: Part 3: 100 mg S-648414 + Dolutegravir

    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.

    Drug: S-648414
    Tablet for oral administration

    Drug: Dolutegravir
    Tablet for oral administration
    Other Names:
  • TIVICAY

    		•
    Experimental: Part 3: 200 mg S-648414 + Dolutegravir

    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.

    Drug: S-648414
    Tablet for oral administration

    Drug: Dolutegravir
    Tablet for oral administration
    Other Names:
  • TIVICAY

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From dosing on Day 1 or Day 14 up to 10 days post dose]

      A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.

    2. Part 2: Number of Participants With Treatment-emergent Adverse Events [From the first dose up to 10 days after end of dosing (25 days); A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment.]

      A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.

    3. Part 3: Number of Participants With Treatment-emergent Adverse Events [From the first dose up to Day 36; A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment.]

      A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.

    4. Part 3: Maximum Plasma Concentration (Cmax) of S-648414 [Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).

    5. Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414 [Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).

    6. Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ) [Day 22 and Day 29 (24 hours post-dosing on Days 21 and 28)]

      The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).

    7. Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414 [Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method.

    8. Part 3: Apparent Total Clearance (CL/F) of S-648414 [Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). Apparent total clearance was calculated as CL/F = Dose/AUC0-τ

    9. Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir [Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.]

      The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.

    10. Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir [Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.]

      The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.

    11. Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ) [Day 8 and Day 29 (24 hours post-dosing on Day 7 and Day 28).]

      The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.

    12. Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir [Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.]

      The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method.

    13. Part 3: Apparent Total Clearance (CL/F) of Dolutegravir [Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.]

      The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. Apparent total clearance calculated as CL/F =Dose/AUC0-τ

    Secondary Outcome Measures

    1. Part 1: Maximum Plasma Concentration (Cmax) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

    2. Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

    3. Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

      Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing, calculated by the linear trapezoidal method when concentrations are increasing and by the logarithmic trapezoidal method when concentrations are decreasing (linear up/log down trapezoidal method).

    4. Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

      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.

    5. Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

      Terminal elimination half-life calculated as t1/2,z = (ln2)/λz, where λz is the terminal elimination rate constant.

    6. Part 1: Terminal Elimination Rate Constant (λz) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

    7. Part 1: Mean Residence Time (MRT) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

      Mean residence time, calculated as MRT = AUMC0-inf / AUC0-inf, where AUMC0-inf is the area under the first moment curve extrapolated to infinity.

    8. Part 1: Apparent Total Clearance (CL/F) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

      Apparent total clearance estimated according to: CL/F = Dose / AUC0-inf.

    9. Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.]

      Apparent volume of distribution in the terminal elimination phase was estimated according to: Vz /F = Dose / AUC0-inf / λz.

    10. Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose]

      The fraction of S-648414 dose excreted in urine from 0 to 96 hours postdose was calculated as: Cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / Dose × 100

    11. Part 1: Renal Clearance (CLR) of S-648414 [Day 1 and Day 14 (for participants in the 100 mg dose group only) predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose]

      Renal clearance was estimated according to: CLR = cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last).

    12. Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration [Day 1 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose; Day 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.]

    13. Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration [Day 1 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose; Day 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.]

    14. Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration [Day 1 and day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      Area under the concentration-time curve over the dosing interval (24 hours) on Day 1 and Day 14, calculated by the linear up/log down trapezoidal method.

    15. Part 2: Terminal Elimination Half-life (t1/2,z) of S-648414 Following Multiple-dose Administration [Day 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.]

      Terminal elimination half-life, where t1/2,z = (ln2)/λz on Day 14.

    16. Part 2: Terminal Elimination Rate Constant (λz) of S-648414 Following Multiple-dose Administration [Day 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.]

      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.

    17. Part 2: Apparent Total Clearance (CL/F) of S-648414 Following Multiple-dose Administration [Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      Apparent total clearance estimated according to: CL/F = Dose/AUC0-τ on Day 14

    18. Part 2: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 Following Multiple-dose Administration [Day 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.]

      Apparent volume of distribution in the terminal elimination phase on Day 14, estimated according to: Vz /F = Dose/AUC0-τ/λz

    19. Part 2: Fraction of S-648414 Dose Excreted in Urine Over the Dosing Interval (Feu0- τ) Following Multiple-dose Administration [Day 14 0-24 hours postdose]

      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).

    20. Part 2: Renal Clearance (CLR) of S-648414 Following Multiple-dose Administration [Day 14 0-24 hours postdose]

      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)

    21. Part 2: Maximum Plasma Concentration (Cmax) of Midazolam [Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

    22. Part 2: Time to Maximum Plasma Concentration of Midazolam [Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

    23. Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam [Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). 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.

    24. Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam [Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). 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.

    25. Part 2: Terminal Elimination Half-life for Midazolam [Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

    26. Part 2: Terminal Elimination Rate Constant for Midazolam [Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

    27. Part 2: Mean Residence Time for Midazolam [Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.]

      The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). Mean residence time was calculated as MRT = AUMC0-inf/AUC0-inf where AUMC0-inf is the area under the first moment curve extrapolated to infinity.

    28. Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) [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.]

      Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QT interval is a measure between Q and T wave in heart's electrical cycle. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate.

    29. Parts 1: Change From Baseline in Heart Rate (HR) [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.]

      Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in HR (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate.

    30. Part 1: Change From Baseline in PR Interval [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.]

      Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in PR interval (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate.

    31. Part 1: Change From Baseline in QRS Interval [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.]

      Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in QRS interval (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate.

    32. Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval [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.]

      Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF in the S-648414 group minus adjusted mean ΔQTcF in the placebo group at each time point.

    33. Part 1: Placebo-corrected Change From Baseline in Heart Rate [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.]

      Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate. Placebo-corrected ΔHR (ΔΔHR) was calculated as the adjusted mean ΔHR in the S-648414 group minus adjusted mean ΔHR in the placebo group at each time point.

    34. Part 1: Placebo-corrected Change From Baseline in PR Interval [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.]

      Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR interval in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate. Placebo-corrected ΔPR (ΔΔPR) was calculated as the adjusted mean ΔPR in the S-648414 group minus adjusted mean ΔPR in the placebo group at each time point.

    35. Part 1: Placebo-corrected Change From Baseline in QRS Duration [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.]

      Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS duration in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in QRS duration (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate. Placebo-corrected ΔQRS (ΔΔQRS) was calculated as the adjusted mean ΔQRS in the S-648414 group minus adjusted mean ΔQRS in the placebo group at each time point.

    36. Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS [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.]

      A participant was determined as an outlier if the following criteria (assessed separately) were met for the ECG intervals at any time point: QTcF: Treatment-emergent value of > 450 and ≤ 480 ms when not present at Baseline (new onset) Treatment-emergent value of > 480 and ≤ 500 ms when not present at Baseline (new onset) Treatment-emergent value of > 500 ms when not present at Baseline (new onset) Increase of QTcF (ΔQTcF) from Baseline of > 30 and ≤ 60 ms Increase of QTcF from Baseline > 60 ms HR: Decrease of HR from Baseline > 25% resulting in HR < 50 bpm Increase of HR from Baseline > 25% resulting in HR > 100 bpm PR: Increase of PR from Baseline > 25% resulting in PR > 200 ms QRS: Increase of QRS from Baseline > 25% resulting in QRS > 120 ms

    37. Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence [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.]

      T-wave abnormalities were categorized as follows: 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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 55 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    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).
    1. Specific to Japan sites: enrollment in Part 3 (Group I and J) will consist of only White or Black or African American race.

    1. Capable of giving signed informed consent

    2. Body mass index (BMI) ≥ 18.5 to < 32.0 kg/m² at the Screening visit．

    3. 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 electrocardiogram (ECG) at Screening and at upon admission to the Clinical Research Unit (CRU) and prior to administration of study intervention on Day 1.

    4. Female study participants must not be a woman of childbearing potential 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.

    5. Male study participants must agree to use contraception during the treatment period and for at least 3 months after the last dose of study intervention.

    Exclusion Criteria:

    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 non-melanoma skin cancers.

    3. Risk factors for:

    4. Torsades de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT Syndrome or Brugada Syndrome)

    5. 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

    6. 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).

    7. History of hypersensitivity or severe side effects induced by a drug.

    8. Any condition requiring medication and/or other treatment, such as dietary restriction and physical therapy.

    9. 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).

    10. 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.

    11. 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.

    12. 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).

    13. 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).

    14. 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.]).

    15. A positive drug or alcohol screen at the Screening visit or upon admission to the CRU.

    16. Used tobacco- or nicotine-containing products (including cigarette, pipe, cigar, chewing, nicotine patch, nicotine gum, or Vaping product) 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).

    17. 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).

    18. 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.

    19. 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.

    20. 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.

    21. 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.

    22. 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.

    23. Previously received S-648414.

    24. Poor venous access.

    25. Donated blood 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.

    26. Considered inappropriate for participation in the study for any reason by the investigator or subinvestigator.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 PPD Ph 1 Clinical Research Unit Austin Texas United States 78744
    2 P-One Clinic Hachioji City Toyko Japan 192-0071

    Sponsors and Collaborators

    • Shionogi

    Investigators

    • Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line, Shionogi

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Shionogi
    ClinicalTrials.gov Identifier:
    NCT04147715
    Other Study ID Numbers:
    • 1908T0911
    First Posted:
    Nov 1, 2019
    Last Update Posted:
    Nov 1, 2021
    Last Verified:
    Oct 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Shionogi
    Pharmacokinetics
    S-648414
    Food effect
    Antiretroviral
    Drug-drug interaction
    Additional relevant MeSH terms:
    Dolutegravir
    Midazolam

    Study Results

    Participant Flow

    Recruitment Details The study consisted of Part 1 (single ascending dose [SAD], food effect, and effects on electrocardiogram [ECG] parameters), Part 2 (multiple ascending dose [MAD] and drug-drug interaction with midazolam, a CYP3A substrate), and Part 3 (the effect of S-648414 on the pharmacokinetics (PK) of dolutegravir and the effect of dolutegravir on the PK of S-648414). Parts 1 and 2 were conducted at a single site in the United States, and Part 3 was conducted at a single site in Japan.
    Pre-assignment Detail In Part 1 healthy participants were sequentially assigned to 1 of 6 ascending dose groups; within each dose group participants were randomized in a 3:1 ratio (4:1 in the 100 mg dose group) to receive S-648414 or placebo. In Part 2 healthy participants were assigned to 1 of 2 dose groups with 8 study participants randomized to receive S-648414 and 2 study participants receiving placebo per group. In Part 3 healthy participants were enrolled in 1 of 2 dose groups.
    Arm/Group Title Part 1: Placebo Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414 Part 2: Placebo + Midazolam Part 2: 50 mg S-648414 + Midazolam Part 2: 30 mg S-648414 + Midazolam Part 3: 100 mg S-648414 + Dolutegravir Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants received a single oral dose of matching placebo to S-648414 in a fasted state on Day 1. Two participants assigned to the 100 mg dose cohort also received a single oral dose of matching placebo in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. 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. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1. Participants received matching placebo to 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 placebo dose on Day 14. 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. 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. 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. 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.
    Period Title: Overall Study
    STARTED 12 6 6 8 6 6 6 4 8 8 14 14
    COMPLETED 12 6 6 8 6 6 6 2 7 8 14 14
    NOT COMPLETED 0 0 0 0 0 0 0 2 1 0 0 0

    Baseline Characteristics

    Arm/Group Title Part 1: Placebo Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414 Part 2: Placebo + Midazolam Part 2: 50 mg S-648414 + Midazolam Part 2: 30 mg S-648414 + Midazolam Part 3: 100 mg S-648414 + Dolutegravir Part 3: 200 mg S-648414 + Dolutegravir Total
    Arm/Group Description Participants received a single oral dose of matching placebo to S-648414 in a fasted state on Day 1. Two participants assigned to the 100 mg dose cohort also received a single oral dose of matching placebo in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. 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. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1. Participants received matching placebo to 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 placebo dose on Day 14. 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. 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. 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. 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. Total of all reporting groups
    Overall Participants 12 6 6 8 6 6 6 4 8 8 14 14 98
    Age (years) [Mean (Standard Deviation) ]
    Part 1
    33.3
    (8.53)
    38.0
    (10.55)
    40.3
    (8.98)
    35.5
    (7.80)
    28.5
    (5.68)
    32.5
    (14.87)
    36.5
    (11.22)
    34.8
    (9.74)
    Part 2
    36.0
    (10.03)
    37.3
    (9.97)
    34.4
    (7.03)
    35.9
    (8.51)
    Part 3
    35.4
    (6.70)
    34.9
    (6.32)
    35.1
    (6.40)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    1
    16.7%
    1
    16.7%
    1
    12.5%
    0
    0%
    2
    33.3%
    1
    16.7%
    1
    25%
    2
    25%
    1
    12.5%
    0
    0%
    0
    0%
    10
    10.2%
    Male
    12
    100%
    5
    83.3%
    5
    83.3%
    7
    87.5%
    6
    100%
    4
    66.7%
    5
    83.3%
    3
    75%
    6
    75%
    7
    87.5%
    14
    100%
    14
    100%
    88
    89.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    5
    41.7%
    1
    16.7%
    3
    50%
    4
    50%
    1
    16.7%
    2
    33.3%
    3
    50%
    0
    0%
    3
    37.5%
    3
    37.5%
    2
    14.3%
    0
    0%
    27
    27.6%
    Not Hispanic or Latino
    7
    58.3%
    5
    83.3%
    3
    50%
    4
    50%
    5
    83.3%
    4
    66.7%
    3
    50%
    4
    100%
    5
    62.5%
    5
    62.5%
    12
    85.7%
    14
    100%
    71
    72.4%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    8.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1%
    Black or African American
    5
    41.7%
    3
    50%
    2
    33.3%
    3
    37.5%
    4
    66.7%
    2
    33.3%
    2
    33.3%
    2
    50%
    3
    37.5%
    5
    62.5%
    2
    14.3%
    6
    42.9%
    39
    39.8%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White
    6
    50%
    3
    50%
    4
    66.7%
    5
    62.5%
    2
    33.3%
    4
    66.7%
    4
    66.7%
    2
    50%
    5
    62.5%
    3
    37.5%
    12
    85.7%
    8
    57.1%
    58
    59.2%
    Other
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
    Description A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.
    Time Frame From dosing on Day 1 or Day 14 up to 10 days post dose

    Outcome Measure Data

    Analysis Population Description
    The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.
    Arm/Group Title Part 1: Placebo - Fasted Part 1: Placebo - Fed Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of matching placebo to S-648414 in a fasted state on Day 1. Participants received a single dose of matching placebo to S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 12 2 6 6 8 8 6 6 6
    Any treatment-emergent adverse event (TEAE)
    2
    16.7%
    0
    0%
    0
    0%
    1
    12.5%
    2
    33.3%
    2
    33.3%
    1
    16.7%
    1
    25%
    2
    25%
    Any treatment-related TEAE
    1
    8.3%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    1
    16.7%
    0
    0%
    0
    0%
    2
    25%
    Any TEAE with severity Grade 2 to 4
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    Any TEAE with severity Grade 3 to 4
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any gastrointestinal AEs
    1
    8.3%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    1
    16.7%
    0
    0%
    0
    0%
    2
    25%
    Any ocular AEs
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Serious adverse events (SAEs)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any treatment-related SAE
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any TEAE leading to study discontinuation
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any TEAE leading to study drug discontinuation
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Deaths
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Part 2: Number of Participants With Treatment-emergent Adverse Events
    Description A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.
    Time Frame From the first dose up to 10 days after end of dosing (25 days); A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment.

    Outcome Measure Data

    Analysis Population Description
    The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.
    Arm/Group Title Part 2: Midazolam (Day -2) Part 2: Placebo (Days 1-13) Part 2: 50 mg S-648414 (Days 1-13) Part 2: 30 mg S-648414 (Days 1-13) Part 2: Placebo + Midazolam (Day 14) Part 2: 50 mg S-648414 + Midazolam (Day 14) Part 2: 30 mg S-648414 + Midazolam (Day 14)
    Arm/Group Description Participants received a single oral dose of 5 mg midazolam on Day -2. Participants received matching placebo to S-648414 orally once a day on Days 1 to 13. Participants received 50 mg S-648414 orally once a day on Days 1 to 13. Participants received 30 mg S-648414 orally once a day on Days 1 to 13. Participants received matching placebo to S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14.
    Measure Participants 20 4 8 8 2 7 8
    Any TEAE
    0
    0%
    2
    33.3%
    2
    33.3%
    3
    37.5%
    0
    0%
    1
    16.7%
    1
    16.7%
    Any treatment-related TEAE
    0
    0%
    2
    33.3%
    2
    33.3%
    2
    25%
    0
    0%
    1
    16.7%
    0
    0%
    Any TEAE with severity Grade 2 to 4
    0
    0%
    2
    33.3%
    2
    33.3%
    1
    12.5%
    0
    0%
    0
    0%
    0
    0%
    Any TEAE with severity Grade 3 to 4
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any gastrointestinal AEs
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any ocular AEs
    0
    0%
    1
    16.7%
    0
    0%
    2
    25%
    0
    0%
    0
    0%
    0
    0%
    Any serious adverse events
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any treatment-related SAEs
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any TEAE leading to study discontinuation
    0
    0%
    2
    33.3%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any TEAE leading to study drug discontinuation
    0
    0%
    2
    33.3%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Deaths
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3. Primary Outcome
    Title Part 3: Number of Participants With Treatment-emergent Adverse Events
    Description A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.
    Time Frame From the first dose up to Day 36; A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment.

    Outcome Measure Data

    Analysis Population Description
    The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.
    Arm/Group Title Part 3: Dolutegravir (100 mg S-648414 Group) Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir (200 mg S-648414 Group) Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants assigned to the 100 mg S-648414 dose group received 50 mg dolutegravir orally once a day on Days 1 to 7. Participants received 100 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants assigned to the 200 mg S-648414 dose group received 50 mg dolutegravir once a day on Days 1 to 7. Participants received 200 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14 14 14
    Any TEAE
    3
    25%
    3
    50%
    4
    66.7%
    2
    25%
    5
    83.3%
    2
    33.3%
    Any treatment-related TEAE
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    33.3%
    1
    16.7%
    Any TEAE with severity Grade 2 to 4
    2
    16.7%
    2
    33.3%
    2
    33.3%
    2
    25%
    3
    50%
    1
    16.7%
    Any TEAE with severity Grade 3 to 4
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any gastrointestinal AEs
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    Any ocular AEs
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    33.3%
    0
    0%
    Any serious adverse events
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any treatment-related SAE
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any TEAE leading to study discontinuation
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Any TEAE leading to study drug discontinuation
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Deaths
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4. Primary Outcome
    Title Part 3: Maximum Plasma Concentration (Cmax) of S-648414
    Description The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).
    Time Frame Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population includes all study participants with at least 1 PK parameter estimated appropriately.
    Arm/Group Title Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants received 100 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants received 200 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    2740
    (20.3)
    2720
    (21.3)
    5150
    (14.1)
    5020
    (15.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of dolutegravir on the PK of S-648414 was assessed by analysis of variance (ANOVA) fit with a linear mixed effect model with the natural log (ln)-transformed Cmax as the dependent variable, treatment as fixed effect, and participant as random effect. The difference and 90% confidence interval (CI) between the ln-transformed Cmax of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of S-648414 were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.9913
    Confidence Interval (2-Sided) 90%
    0.9232 to 1.0645
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / S-648414
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of dolutegravir on the PK of S-648414 was assessed by an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cmax as the dependent variable, treatment as fixed effect, and participant as random effect. The difference and 90% CI between the ln-transformed Cmax of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of S-648414 were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.9754
    Confidence Interval (2-Sided) 90%
    0.8916 to 1.0671
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / S-648414
    5. Primary Outcome
    Title Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414
    Description The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).
    Time Frame Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants received 100 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants received 200 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Median (Full Range) [hours]
    2.00
    2.25
    2.50
    2.25
    6. Primary Outcome
    Title Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ)
    Description The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).
    Time Frame Day 22 and Day 29 (24 hours post-dosing on Days 21 and 28)

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants received 100 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants received 200 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    1210
    (27.7)
    1250
    (16.3)
    2590
    (16.5)
    2360
    (14.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of dolutegravir on the PK of S-648414 was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cτ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cτ of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of S-648414 were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.0353
    Confidence Interval (2-Sided) 90%
    0.9421 to 1.1377
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / S-648414
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of dolutegravir on the PK of S-648414 was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cτ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cτ of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of S-648414 were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.9096
    Confidence Interval (2-Sided) 90%
    0.8791 to 0.9411
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / S-648414
    7. Primary Outcome
    Title Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414
    Description The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method.
    Time Frame Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants received 100 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants received 200 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    40800
    (17.6)
    41080
    (15.4)
    81010
    (11.4)
    79820
    (12.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of dolutegravir on the PK of S-648414 was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed AUC0-τ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of S-648414 were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.0071
    Confidence Interval (2-Sided) 90%
    0.9679 to 1.0479
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / S-648414
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of dolutegravir on the PK of S-648414 was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed AUC0-τ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of S-648414 were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.9852
    Confidence Interval (2-Sided) 90%
    0.9605 to 1.0105
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / S-648414
    8. Primary Outcome
    Title Part 3: Apparent Total Clearance (CL/F) of S-648414
    Description The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). Apparent total clearance was calculated as CL/F = Dose/AUC0-τ
    Time Frame Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants received 100 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants received 200 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    2.45
    (17.6)
    2.43
    (15.4)
    2.47
    (11.4)
    2.51
    (12.5)
    9. Primary Outcome
    Title Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir
    Description The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.
    Time Frame Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: Dolutegravir (100 mg S-648414 Group) Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir (200 mg S-648414 Group) Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants assigned to the 100 mg S-648414 dose group received 50 mg dolutegravir orally once a day on Days 1 to 7. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants assigned to the 200 mg S-648414 dose group received 50 mg dolutegravir once a day on Days 1 to 7. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    4910
    (15.9)
    5800
    (12.2)
    4720
    (19.6)
    4950
    (15.9)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of dolutegravir were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.1806
    Confidence Interval (2-Sided) 90%
    1.1171 to 1.2477
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / Dolutegravir
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of dolutegravir were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.0480
    Confidence Interval (2-Sided) 90%
    0.9656 to 1.1373
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / Dolutegravir
    10. Primary Outcome
    Title Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir
    Description The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.
    Time Frame Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: Dolutegravir (100 mg S-648414 Group) Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir (200 mg S-648414 Group) Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants assigned to the 100 mg S-648414 dose group received 50 mg dolutegravir orally once a day on Days 1 to 7. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants assigned to the 200 mg S-648414 dose group received 50 mg dolutegravir once a day on Days 1 to 7. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Median (Full Range) [hours]
    3.50
    2.75
    3.50
    4.00
    11. Primary Outcome
    Title Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ)
    Description The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.
    Time Frame Day 8 and Day 29 (24 hours post-dosing on Day 7 and Day 28).

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: Dolutegravir (100 mg S-648414 Group) Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir (200 mg S-648414 Group) Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants assigned to the 100 mg S-648414 dose group received 50 mg dolutegravir orally once a day on Days 1 to 7. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants assigned to the 200 mg S-648414 dose group received 50 mg dolutegravir once a day on Days 1 to 7. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    1980
    (23.1)
    2660
    (17.6)
    1850
    (25.7)
    2000
    (23.9)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cτ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cτ of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of dolutegravir were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.3445
    Confidence Interval (2-Sided) 90%
    1.2352 to 1.4636
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / Dolutegravir
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cτ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cτ of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of dolutegravir were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.0769
    Confidence Interval (2-Sided) 90%
    1.0137 to 1.1441
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / Dolutegravir
    12. Primary Outcome
    Title Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir
    Description The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method.
    Time Frame Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: Dolutegravir (100 mg S-648414 Group) Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir (200 mg S-648414 Group) Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants assigned to the 100 mg S-648414 dose group received 50 mg dolutegravir orally once a day on Days 1 to 7. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants assigned to the 200 mg S-648414 dose group received 50 mg dolutegravir once a day on Days 1 to 7. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    74790
    (19.7)
    89290
    (13.4)
    69850
    (20.1)
    73210
    (17.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed AUC0-τ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of dolutegravir were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.1939
    Confidence Interval (2-Sided) 90%
    1.1176 to 1.2754
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / Dolutegravir
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed AUC0-τ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, Cτ, and AUC0-τ of dolutegravir were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.0482
    Confidence Interval (2-Sided) 90%
    0.9881 to 1.1119
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = S-648414 + Dolutegravir / Dolutegravir
    13. Primary Outcome
    Title Part 3: Apparent Total Clearance (CL/F) of Dolutegravir
    Description The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. Apparent total clearance calculated as CL/F =Dose/AUC0-τ
    Time Frame Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 3: Dolutegravir (100 mg S-648414 Group) Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir (200 mg S-648414 Group) Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants assigned to the 100 mg S-648414 dose group received 50 mg dolutegravir orally once a day on Days 1 to 7. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants assigned to the 200 mg S-648414 dose group received 50 mg dolutegravir once a day on Days 1 to 7. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    Measure Participants 14 14 14 14
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    0.669
    (19.7)
    0.560
    (13.4)
    0.716
    (20.1)
    0.683
    (17.6)
    14. Secondary Outcome
    Title Part 1: Maximum Plasma Concentration (Cmax) of S-648414
    Description
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    151
    (22.8)
    498
    (17.7)
    1620
    (13.1)
    1430
    (18.0)
    3820
    (25.7)
    9260
    (31.9)
    12700
    (26.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed, Part 1: 10 mg S-648414, Part 1: 100 mg S-648414 Fasted, Part 1: 100 mg S-648414 Fed, Part 1: 250 mg S-648414
    Comments The dose proportionality of plasma PK parameters of S-648414 was examined for all fasted groups in Part 1 using the power model. The power model assumes a linear relationship between the ln-transformed parameter and ln-transformed dose where ln(Cmax) = Intercept + Slope × ln(Dose) + Random error
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value 0.9857
    Confidence Interval (2-Sided) 95%
    0.9341 to 1.0373
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of food on the plasma PK of S-648414 was examined after a single dose of 100 mg S-648414 in the fed state and fasted state using an ANOVA fitted with a linear mixed effect model with ln-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as random effect. The difference and 90% CI between the fed and fasted state ln-transformed Cmax were estimated, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.8786
    Confidence Interval (2-Sided) 90%
    0.7705 to 1.0019
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = Fed / Fasted
    15. Secondary Outcome
    Title Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414
    Description
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Median (Full Range) [hours]
    1.00
    1.00
    1.25
    3.00
    1.50
    1.50
    1.75
    16. Secondary Outcome
    Title Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414
    Description Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing, calculated by the linear trapezoidal method when concentrations are increasing and by the logarithmic trapezoidal method when concentrations are decreasing (linear up/log down trapezoidal method).
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    3431
    (18.1)
    10610
    (19.3)
    36370
    (9.2)
    34910
    (14.2)
    89330
    (20.2)
    215300
    (27.1)
    359300
    (23.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed, Part 1: 10 mg S-648414, Part 1: 100 mg S-648414 Fasted, Part 1: 100 mg S-648414 Fed, Part 1: 250 mg S-648414
    Comments The dose proportionality of plasma PK parameters of S-648414 was examined for all fasted groups in Part 1 using the power model. The power model assumes a linear relationship between the ln-transformed parameter and ln-transformed dose where ln(AUC0-last) = Intercept + Slope × ln(Dose) + Random error
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value 1.0252
    Confidence Interval (2-Sided) 95%
    0.9840 to 1.0665
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of food on the plasma PK of S-648414 was examined after a single dose of 100 mg S-648414 in the fed and fasted state using an ANOVA fitted with a linear mixed effect model, with ln-transformed AUC0-last as the dependent variable, treatment as a fixed effect, and participant as random effect. The difference and 90% CI between the fed and fasted state ln-transformed AUC0-last were estimated, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.9598
    Confidence Interval (2-Sided) 90%
    0.8585 to 1.0730
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = Fed / Fasted
    17. Secondary Outcome
    Title Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414
    Description 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.
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    3620
    (17.5)
    11040
    (19.6)
    38300
    (10.9)
    36940
    (14.4)
    95510
    (21.0)
    226600
    (26.5)
    382000
    (23.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed, Part 1: 10 mg S-648414, Part 1: 100 mg S-648414 Fasted, Part 1: 100 mg S-648414 Fed, Part 1: 250 mg S-648414
    Comments The dose proportionality of plasma PK parameters of S-648414 was examined for all fasted groups in Part 1 using the power model. The power model assumes a linear relationship between the ln-transformed parameter and ln-transformed dose where ln(AUC0-inf) = Intercept + Slope × ln(Dose) + Random error
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value 1.0280
    Confidence Interval (2-Sided) 95%
    0.9866 to 1.0695
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of food on the plasma PK of S-648414 was examined after a single dose of 100 mg S-648414 in the fed and fasted state using an ANOVA fitted with a linear mixed effect model, with ln-transformed AUC0-inf as the dependent variable, treatment as a fixed effect, and participant as random effect. The difference and 90% CI between the fed and fasted state ln-transformed AUC0-inf were estimated, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.9646
    Confidence Interval (2-Sided) 90%
    0.8643 to 1.0766
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = Fed / Fasted
    18. Secondary Outcome
    Title Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414
    Description Terminal elimination half-life calculated as t1/2,z = (ln2)/λz, where λz is the terminal elimination rate constant.
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    23.0
    (5.0)
    20.7
    (9.9)
    22.2
    (16.0)
    22.8
    (14.2)
    24.1
    (12.1)
    22.2
    (12.1)
    23.7
    (14.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of food on the plasma PK of S-648414 was examined after a single dose of 100 mg S-648414 in the fed and fasted state using an ANOVA fitted with a linear mixed effect model, with ln-transformed t1/2,z as the dependent variable, treatment as a fixed effect, and participant as random effect. The difference and 90% CI between the fed and fasted state ln-transformed t1/2,z were estimated, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.0272
    Confidence Interval (2-Sided) 90%
    0.9949 to 1.0606
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = Fed / Fasted
    19. Secondary Outcome
    Title Part 1: Terminal Elimination Rate Constant (λz) of S-648414
    Description
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [1/hour]
    0.0301
    (5.0)
    0.0336
    (9.9)
    0.0313
    (16.0)
    0.0305
    (14.2)
    0.0288
    (12.1)
    0.0312
    (12.1)
    0.0293
    (14.2)
    20. Secondary Outcome
    Title Part 1: Mean Residence Time (MRT) of S-648414
    Description Mean residence time, calculated as MRT = AUMC0-inf / AUC0-inf, where AUMC0-inf is the area under the first moment curve extrapolated to infinity.
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    32.5
    (4.3)
    29.2
    (9.5)
    31.5
    (16.1)
    33.8
    (14.6)
    34.2
    (12.6)
    32.6
    (12.9)
    34.5
    (13.3)
    21. Secondary Outcome
    Title Part 1: Apparent Total Clearance (CL/F) of S-648414
    Description Apparent total clearance estimated according to: CL/F = Dose / AUC0-inf.
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    2.76
    (17.5)
    2.72
    (19.6)
    2.61
    (10.9)
    2.71
    (14.4)
    2.62
    (21.0)
    2.21
    (26.5)
    2.62
    (23.6)
    22. Secondary Outcome
    Title Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414
    Description Apparent volume of distribution in the terminal elimination phase was estimated according to: Vz /F = Dose / AUC0-inf / λz.
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [liters]
    91.7
    (21.2)
    81.0
    (21.2)
    83.5
    (11.0)
    88.9
    (19.5)
    91.0
    (17.3)
    70.8
    (31.7)
    89.3
    (23.9)
    23. Secondary Outcome
    Title Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96)
    Description The fraction of S-648414 dose excreted in urine from 0 to 96 hours postdose was calculated as: Cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / Dose × 100
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [percent excreted]
    30.3
    (22.6)
    25.5
    (20.1)
    25.3
    (19.2)
    25.1
    (11.1)
    28.7
    (19.8)
    31.5
    (10.2)
    25.9
    (27.3)
    24. Secondary Outcome
    Title Part 1: Renal Clearance (CLR) of S-648414
    Description Renal clearance was estimated according to: CLR = cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last).
    Time Frame Day 1 and Day 14 (for participants in the 100 mg dose group only) predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK parameter population
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 8 6 6 6
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    0.884
    (11.6)
    0.721
    (25.9)
    0.695
    (17.5)
    0.720
    (18.4)
    0.804
    (10.3)
    0.732
    (30.6)
    0.720
    (24.3)
    25. Secondary Outcome
    Title Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration
    Description
    Time Frame Day 1 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose; Day 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.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data at each time point
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 8
    Day 1
    411
    (22.3)
    623
    (19.2)
    Day 14
    719
    (13.2)
    1320
    (20.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The dose proportionality of plasma S-648414 Cmax after a single dose of S-648414 (Day 1) was assessed using an ANOVA model fitted to the ln-transformed Cmax, with dose group fitted as a fixed factor. The point estimates and 90% CIs were generated for the ratios of the 50 mg dose to 30 mg dose ln-transformed Cmax, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.5167
    Confidence Interval (2-Sided) 90%
    1.2654 to 1.8180
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 50 mg / 30 mg
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The dose proportionality of plasma S-648414 Cmax after multiple doses of S-648414 (Day 14) was assessed using an ANOVA model fitted to the ln-transformed Cmax, with dose group fitted as a fixed factor. The point estimates and 90% CIs were generated for the ratios of the 50 mg dose to 30 mg dose ln-transformed Cmax, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.8372
    Confidence Interval (2-Sided) 90%
    1.5696 to 2.1506
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 50 mg / 30 mg
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted
    Comments The accumulation ratio of Cmax in the 30 mg dose group was calculated as the ratio of Day 14 to Day 1 using an ANOVA fitted with a linear mixed model with ln-transformed Cmax, Day as a fixed effect and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax on Day 1 and Day 14 were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.7489
    Confidence Interval (2-Sided) 90%
    1.5250 to 2.0057
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = Day 14 / Day 1
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fed
    Comments The accumulation ratio of Cmax in the 50 mg dose group was calculated as the ratio of Day 14 to Day 1 using an ANOVA fitted with a linear mixed model with ln-transformed Cmax, Day as a fixed effect and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax on Day 1 and Day 14 were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 2.1453
    Confidence Interval (2-Sided) 90%
    1.9741 to 2.3313
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = Day 14 / Day 1
    26. Secondary Outcome
    Title Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration
    Description
    Time Frame Day 1 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose; Day 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.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data at each time point
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 8
    Day 1
    3.02
    4.50
    Day 14
    2.03
    1.25
    27. Secondary Outcome
    Title Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration
    Description Area under the concentration-time curve over the dosing interval (24 hours) on Day 1 and Day 14, calculated by the linear up/log down trapezoidal method.
    Time Frame Day 1 and day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data at each time point
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 8
    Day 1
    5519
    (15.9)
    8983
    (17.9)
    Day 14
    10540
    (14.9)
    18400
    (20.4)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The dose proportionality of plasma S-648414 AUC0-τ after a single dose of S-648414 (Day 1) was assessed using an ANOVA model fitted to the ln-transformed AUC0-τ, with dose group fitted as a fixed factor. The point estimates and 90% CIs were generated for the ratios of the 50 mg dose to 30 mg dose ln-transformed AUC0-τ, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.6277
    Confidence Interval (2-Sided) 90%
    1.4038 to 1.8874
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 50 mg / 30 mg
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The dose proportionality of plasma S-648414 AUC0-τ after multiple doses of S-648414 (Day 14) was assessed using an ANOVA model fitted to the ln-transformed AUC0-τ, with dose group fitted as a fixed factor. The point estimates and 90% CIs were generated for the ratios of the 50 mg dose to 30 mg dose ln-transformed AUC0-τ, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.7454
    Confidence Interval (2-Sided) 90%
    1.4785 to 2.0605
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 50 mg / 30 mg
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted
    Comments The accumulation ratio of AUC0-τ in the 30 mg dose group was calculated as the ratio of Day 14 to Day 1 using an ANOVA fitted with a linear mixed model with ln-transformed AUC0-τ, Day as a fixed effect and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ on Day 1 and Day 14 were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.9102
    Confidence Interval (2-Sided) 90%
    1.7788 to 2.0513
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = Day 14 / Day 1
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fed
    Comments The accumulation ratio of AUC0-τ in the 50 mg dose group was calculated as the ratio of Day 14 to Day 1 using an ANOVA fitted with a linear mixed model with ln-transformed AUC0-τ, Day as a fixed effect and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ on Day 1 and Day 14 were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 2.0478
    Confidence Interval (2-Sided) 90%
    1.9203 to 2.1837
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = Day 14 / Day 1
    28. Secondary Outcome
    Title Part 2: Terminal Elimination Half-life (t1/2,z) of S-648414 Following Multiple-dose Administration
    Description Terminal elimination half-life, where t1/2,z = (ln2)/λz on Day 14.
    Time Frame Day 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.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 6
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    21.6
    (12.5)
    23.7
    (11.0)
    29. Secondary Outcome
    Title Part 2: Terminal Elimination Rate Constant (λz) of S-648414 Following Multiple-dose Administration
    Description 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.
    Time Frame Day 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.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 6
    Geometric Mean (Geometric Coefficient of Variation) [1/hours]
    0.0321
    (12.5)
    0.0292
    (11.0)
    30. Secondary Outcome
    Title Part 2: Apparent Total Clearance (CL/F) of S-648414 Following Multiple-dose Administration
    Description Apparent total clearance estimated according to: CL/F = Dose/AUC0-τ on Day 14
    Time Frame Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 6
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    2.85
    (14.9)
    2.72
    (20.4)
    31. Secondary Outcome
    Title Part 2: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 Following Multiple-dose Administration
    Description Apparent volume of distribution in the terminal elimination phase on Day 14, estimated according to: Vz /F = Dose/AUC0-τ/λz
    Time Frame Day 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.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 6
    Geometric Mean (Geometric Coefficient of Variation) [liters]
    88.7
    (13.6)
    93.0
    (28.5)
    32. Secondary Outcome
    Title Part 2: Fraction of S-648414 Dose Excreted in Urine Over the Dosing Interval (Feu0- τ) Following Multiple-dose Administration
    Description 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).
    Time Frame Day 14 0-24 hours postdose

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 6
    Geometric Mean (Geometric Coefficient of Variation) [percent excreted]
    33.3
    (15.7)
    35.0
    (25.6)
    33. Secondary Outcome
    Title Part 2: Renal Clearance (CLR) of S-648414 Following Multiple-dose Administration
    Description 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)
    Time Frame Day 14 0-24 hours postdose

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: 30 mg S-648414 + Midazolam Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description 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. 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.
    Measure Participants 8 6
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    0.948
    (18.4)
    0.952
    (18.1)
    34. Secondary Outcome
    Title Part 2: Maximum Plasma Concentration (Cmax) of Midazolam
    Description The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).
    Time Frame Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: Midazolam (30 mg S-648414 Group) Part 2: 30 mg S-648414 + Midazolam Part 2: Midazolam (50 mg S-648414 Group) Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description Participants assigned to the 30 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants assigned to the 50 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14.
    Measure Participants 8 8 8 6
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    18.0
    (33.6)
    16.8
    (25.6)
    19.5
    (30.6)
    19.3
    (33.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, AUC0-last, and AUC0-inf of midazolam were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.9241
    Confidence Interval (2-Sided) 90%
    0.8057 to 1.0600
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 30 mg S-648414 + Midazolam / Midazolam
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, AUC0-last, and AUC0-inf of midazolam were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 1.0303
    Confidence Interval (2-Sided) 90%
    0.9299 to 1.1415
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 50 mg S-648414 + Midazolam / Midazolam
    35. Secondary Outcome
    Title Part 2: Time to Maximum Plasma Concentration of Midazolam
    Description The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).
    Time Frame Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: Midazolam (30 mg S-648414 Group) Part 2: 30 mg S-648414 + Midazolam Part 2: Midazolam (50 mg S-648414 Group) Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description Participants assigned to the 30 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants assigned to the 50 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14.
    Measure Participants 8 8 8 6
    Median (Full Range) [hours]
    0.76
    1.00
    0.50
    0.50
    36. Secondary Outcome
    Title Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam
    Description The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). 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.
    Time Frame Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: Midazolam (30 mg S-648414 Group) Part 2: 30 mg S-648414 + Midazolam Part 2: Midazolam (50 mg S-648414 Group) Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description Participants assigned to the 30 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants assigned to the 50 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14.
    Measure Participants 8 8 8 6
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    70.17
    (30.7)
    59.83
    (40.5)
    73.28
    (40.7)
    64.53
    (35.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed AUC0-last as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-last of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, AUC0-last, and AUC0-inf of midazolam were completely contained within the range of 0.8000 to 1.2500
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.8420
    Confidence Interval (2-Sided) 90%
    0.6628 to 1.0696
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 30 mg S-648414 + Midazolam / Midazolam
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed AUC0-last as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-last of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, AUC0-last, and AUC0-inf of midazolam were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.8542
    Confidence Interval (2-Sided) 90%
    0.7185 to 1.0155
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 50 mg S-648414 + Midazolam / Midazolam
    37. Secondary Outcome
    Title Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam
    Description The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). 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.
    Time Frame Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: Midazolam (30 mg S-648414 Group) Part 2: 30 mg S-648414 + Midazolam Part 2: Midazolam (50 mg S-648414 Group) Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description Participants assigned to the 30 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants assigned to the 50 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14.
    Measure Participants 8 8 8 6
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    72.81
    (28.7)
    61.68
    (41.2)
    76.03
    (42.2)
    67.02
    (37.1)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part 1: Placebo - Fasted, Part 1: Placebo - Fed
    Comments The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed AUC0-inf as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-inf of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, AUC0-last, and AUC0-inf of midazolam were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.8377
    Confidence Interval (2-Sided) 90%
    0.6645 to 1.0561
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 30 mg S-648414 + Midazolam / Midazolam
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part 1: 10 mg S-648414, Part 1: 30 mg S-648414
    Comments The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed AUC0-inf as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-inf of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.
    Type of Statistical Test Other
    Comments The drug interaction was assessed by whether the 90% CIs for the geometric least squares mean ratio of Cmax, AUC0-last, and AUC0-inf of midazolam were completely contained within the range of 0.8000 to 1.2500.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Least Squares Mean Ratio
    Estimated Value 0.8529
    Confidence Interval (2-Sided) 90%
    0.7213 to 1.0085
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio = 50 mg S-648414 + Midazolam / Midazolam
    38. Secondary Outcome
    Title Part 2: Terminal Elimination Half-life for Midazolam
    Description The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).
    Time Frame Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: Midazolam (30 mg S-648414 Group) Part 2: 30 mg S-648414 + Midazolam Part 2: Midazolam (50 mg S-648414 Group) Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description Participants assigned to the 30 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants assigned to the 50 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14.
    Measure Participants 8 8 8 6
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    5.07
    (18.7)
    4.64
    (32.4)
    4.41
    (41.1)
    4.54
    (39.5)
    39. Secondary Outcome
    Title Part 2: Terminal Elimination Rate Constant for Midazolam
    Description The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).
    Time Frame Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: Midazolam (30 mg S-648414 Group) Part 2: 30 mg S-648414 + Midazolam Part 2: Midazolam (50 mg S-648414 Group) Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description Participants assigned to the 30 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants assigned to the 50 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14.
    Measure Participants 8 8 8 6
    Geometric Mean (Geometric Coefficient of Variation) [1/hour]
    0.1366
    (18.7)
    0.1494
    (32.4)
    0.1570
    (41.1)
    0.1528
    (39.5)
    40. Secondary Outcome
    Title Part 2: Mean Residence Time for Midazolam
    Description The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). Mean residence time was calculated as MRT = AUMC0-inf/AUC0-inf where AUMC0-inf is the area under the first moment curve extrapolated to infinity.
    Time Frame Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.

    Outcome Measure Data

    Analysis Population Description
    The PK parameter population with available data
    Arm/Group Title Part 2: Midazolam (30 mg S-648414 Group) Part 2: 30 mg S-648414 + Midazolam Part 2: Midazolam (50 mg S-648414 Group) Part 2: 50 mg S-648414 + Midazolam
    Arm/Group Description Participants assigned to the 30 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants assigned to the 50 mg S-648414 dose group received a single oral dose of 5 mg midazolam on Day -2 Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14.
    Measure Participants 8 8 8 6
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    5.30
    (8.6)
    4.44
    (28.3)
    4.93
    (33.8)
    4.40
    (38.0)
    41. Secondary Outcome
    Title Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF)
    Description Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QT interval is a measure between Q and T wave in heart's electrical cycle. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The QT/QTc population included all study participants randomly assigned to study intervention and who took at least 1 dose of study intervention.who had measurements at Baseline as well as on-treatment, with at least 1 post-dose time point with a valid ΔQTcF value. Participants with available data at each time point are included. Cardiodynamic ECG assessments were performed for Part 1 only.
    Arm/Group Title Part 1: Placebo Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of matching placebo in a fasted state on Day 1. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 12 6 6 8 6 6 6
    0.5 hours postdose
    -3.2
    (1.16)
    -3.2
    (1.61)
    -5.6
    (1.61)
    -4.8
    (1.40)
    -4.1
    (1.64)
    -5.6
    (1.69)
    2.0
    (1.62)
    1 hour postdose
    -2.2
    (1.19)
    -0.4
    (1.66)
    -2.4
    (1.66)
    -3.2
    (1.44)
    -0.9
    (1.69)
    -1.0
    (1.74)
    4.9
    (1.67)
    1.5 hours postdose
    -1.1
    (1.40)
    -1.2
    (1.96)
    -2.6
    (1.96)
    -1.1
    (1.69)
    1.8
    (1.98)
    3.1
    (2.02)
    4.9
    (1.96)
    2 hours postdose
    -0.1
    (1.38)
    -2.1
    (1.93)
    -1.0
    (1.93)
    -1.9
    (1.67)
    -1.2
    (1.95)
    2.4
    (1.99)
    6.3
    (1.93)
    2.5 hours postdose
    -2.5
    (1.39)
    -1.7
    (1.94)
    -1.5
    (1.94)
    -1.1
    (1.68)
    0.4
    (1.97)
    2.5
    (2.01)
    8.0
    (1.95)
    3 hours postdose
    -1.9
    (1.24)
    2.3
    (1.73)
    -1.3
    (1.73)
    -0.6
    (1.50)
    2.6
    (1.76)
    -0.4
    (1.80)
    10.1
    (1.74)
    4 hours postdose
    -2.3
    (1.54)
    -0.2
    (2.16)
    -0.6
    (2.16)
    0.1
    (1.87)
    0.2
    (2.18)
    3.6
    (2.22)
    12.0
    (2.17)
    6 hours postdose
    -5.3
    (2.52)
    -12.0
    (3.55)
    -2.3
    (3.56)
    -1.2
    (3.08)
    -4.6
    (3.57)
    -4.6
    (3.59)
    2.9
    (3.56)
    8 hours postdose
    -4.1
    (1.71)
    -6.7
    (2.41)
    -0.3
    (2.41)
    -3.2
    (2.08)
    -5.9
    (2.43)
    -3.4
    (2.46)
    5.0
    (2.41)
    12 hours postdose
    -0.9
    (2.44)
    -1.8
    (3.44)
    0.9
    (3.44)
    1.0
    (2.98)
    -1.3
    (3.45)
    -3.0
    (3.48)
    8.8
    (3.44)
    24 hours postdose
    -1.4
    (1.19)
    -4.9
    (1.66)
    -1.2
    (1.66)
    -2.1
    (1.44)
    -0.8
    (1.69)
    -1.8
    (1.74)
    7.5
    (2.01)
    42. Secondary Outcome
    Title Parts 1: Change From Baseline in Heart Rate (HR)
    Description Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in HR (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The QT/QTc population with available data at each time point
    Arm/Group Title Part 1: Placebo Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of matching placebo in a fasted state on Day 1. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 12 6 6 8 6 6 6
    0.5 hours postdose
    0.9
    (1.11)
    -0.2
    (1.58)
    -1.4
    (1.60)
    -1.1
    (1.36)
    -0.1
    (1.57)
    -0.7
    (1.57)
    -1.6
    (1.57)
    1 hour postdose
    1.5
    (1.16)
    -2.7
    (1.64)
    -1.9
    (1.66)
    -2.1
    (1.41)
    0.4
    (1.64)
    -1.0
    (1.63)
    -0.8
    (1.63)
    1.5 hours postdose
    -0.4
    (1.18)
    -3.0
    (1.67)
    -0.3
    (1.69)
    -3.0
    (1.44)
    -0.5
    (1.67)
    0.2
    (1.67)
    -0.4
    (1.66)
    2 hours postdose
    -0.5
    (1.30)
    -3.2
    (1.85)
    -2.4
    (1.87)
    -2.5
    (1.60)
    -1.7
    (1.85)
    0.4
    (1.85)
    -0.3
    (1.84)
    2.5 hours postdose
    0.8
    (1.28)
    -1.2
    (1.82)
    -3.0
    (1.84)
    -2.2
    (1.57)
    -0.7
    (1.81)
    2.7
    (1.81)
    -0.7
    (1.81)
    3 hours postdose
    -0.9
    (1.38)
    -3.0
    (1.96)
    -1.6
    (1.97)
    -2.1
    (1.69)
    -1.8
    (1.95)
    2.0
    (1.95)
    -0.6
    (1.95)
    4 hours postdose
    0.2
    (1.41)
    -1.2
    (2.00)
    0.7
    (2.02)
    -2.8
    (1.73)
    0.8
    (2.00)
    2.1
    (2.00)
    3.3
    (2.00)
    6 hours postdose
    5.2
    (1.18)
    4.6
    (1.68)
    2.4
    (1.70)
    4.2
    (1.45)
    3.7
    (1.67)
    7.3
    (1.67)
    7.5
    (1.67)
    8 hours postdose
    1.5
    (1.56)
    1.7
    (2.21)
    0.7
    (2.22)
    -0.2
    (1.91)
    1.8
    (2.20)
    4.6
    (2.20)
    3.5
    (2.20)
    12 hours postdose
    2.7
    (1.80)
    1.1
    (2.55)
    1.9
    (2.56)
    1.1
    (2.21)
    2.4
    (2.55)
    9.1
    (2.55)
    3.4
    (2.55)
    24 hours postdose
    0.4
    (1.64)
    -1.7
    (2.33)
    -0.4
    (2.34)
    -1.4
    (2.01)
    0.8
    (2.33)
    0.3
    (2.32)
    3.3
    (2.59)
    43. Secondary Outcome
    Title Part 1: Change From Baseline in PR Interval
    Description Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in PR interval (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The QT/QTc population with available data at each time point
    Arm/Group Title Part 1: Placebo Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of matching placebo in a fasted state on Day 1. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 12 6 6 8 6 6 6
    0.5 hours postdose
    0.4
    (1.29)
    1.0
    (1.87)
    2.2
    (1.83)
    -0.1
    (1.61)
    1.3
    (1.85)
    -3.9
    (1.84)
    0.0
    (1.83)
    1 hour postdose
    0.9
    (1.29)
    1.0
    (1.86)
    4.0
    (1.82)
    1.3
    (1.60)
    1.9
    (1.84)
    -6.4
    (1.83)
    1.0
    (1.82)
    1.5 hours postdose
    0.4
    (1.74)
    3.4
    (2.49)
    1.0
    (2.46)
    0.9
    (2.15)
    2.2
    (2.47)
    0.8
    (2.47)
    0.9
    (2.46)
    2 hours postdose
    0.8
    (1.44)
    2.8
    (2.07)
    3.4
    (2.03)
    -2.3
    (1.78)
    -1.4
    (2.05)
    -2.1
    (2.04)
    0.2
    (2.04)
    2.5 hours postdose
    0.7
    (1.60)
    1.1
    (2.29)
    4.5
    (2.26)
    -0.1
    (1.97)
    0.5
    (2.27)
    -5.2
    (2.26)
    -0.9
    (2.26)
    3 hours postdose
    -0.1
    (1.86)
    3.6
    (2.67)
    3.7
    (2.64)
    1.7
    (2.30)
    -1.5
    (2.65)
    -5.3
    (2.64)
    -0.7
    (2.64)
    4 hours postdose
    0.5
    (1.67)
    3.0
    (2.39)
    3.1
    (2.36)
    -1.0
    (2.06)
    -0.1
    (2.37)
    -6.9
    (2.36)
    -1.7
    (2.36)
    6 hours postdose
    -2.8
    (1.56)
    -1.6
    (2.24)
    0.7
    (2.21)
    -2.3
    (1.93)
    -0.9
    (2.22)
    -7.0
    (2.21)
    -3.0
    (2.21)
    8 hours postdose
    -3.2
    (1.90)
    -1.8
    (2.71)
    3.6
    (2.68)
    -4.5
    (2.34)
    -5.8
    (2.69)
    -5.8
    (2.69)
    -1.8
    (2.68)
    12 hours postdose
    -0.9
    (2.12)
    0.4
    (3.03)
    3.5
    (3.00)
    -1.3
    (2.61)
    -1.0
    (3.01)
    -7.8
    (3.01)
    -0.5
    (3.01)
    24 hours postdose
    -1.5
    (1.61)
    0.1
    (2.32)
    0.8
    (2.28)
    0.5
    (1.99)
    -4.2
    (2.29)
    -2.2
    (2.29)
    -3.1
    (2.52)
    44. Secondary Outcome
    Title Part 1: Change From Baseline in QRS Interval
    Description Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in QRS interval (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The QT/QTc population with available data at each time point
    Arm/Group Title Part 1: Placebo Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of matching placebo in a fasted state on Day 1. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 12 6 6 8 6 6 6
    0.5 hours postdose
    -0.3
    (0.21)
    0.0
    (0.31)
    -0.4
    (0.30)
    0.2
    (0.26)
    -0.1
    (0.31)
    0.1
    (0.30)
    -.1
    (0.31)
    1 hour postdose
    -0.4
    (0.22)
    -0.1
    (0.32)
    0.1
    (0.32)
    0.2
    (0.27)
    0.3
    (0.32)
    0.2
    (0.32)
    0.4
    (0.32)
    1.5 hours postdose
    0.5
    (0.45)
    -0.2
    (0.63)
    0.0
    (0.63)
    0.4
    (0.55)
    0.5
    (0.63)
    0.3
    (0.63)
    0.6
    (0.63)
    2 hours postdose
    -0.3
    (0.24)
    0.2
    (0.34)
    0.1
    (0.34)
    0.7
    (0.29)
    0.1
    (0.34)
    0.4
    (0.34)
    0.8
    (0.34)
    2.5 hours postdose
    -0.1
    (0.24)
    0.0
    (0.34)
    0.2
    (0.34)
    -0.2
    (0.30)
    0.2
    (0.34)
    0.0
    (0.34)
    0.3
    (0.34)
    3 hours postdose
    -0.2
    (0.22)
    0.0
    (0.31)
    0.2
    (0.31)
    0.1
    (0.27)
    0.4
    (0.31)
    0.4
    (0.31)
    0.2
    (0.31)
    4 hours postdose
    0.2
    (0.29)
    -0.1
    (0.41)
    0.2
    (0.41)
    0.5
    (0.35)
    0.3
    (0.41)
    0.9
    (0.41)
    1.0
    (0.41)
    6 hours postdose
    -0.5
    (0.55)
    -0.8
    (0.78)
    -0.5
    (0.77)
    -0.7
    (0.67)
    -1.3
    (0.78)
    0.6
    (0.77)
    0.8
    (0.78)
    8 hours postdose
    -0.8
    (0.33)
    -0.6
    (0.47)
    -0.2
    (0.47)
    -0.3
    (0.41)
    -0.3
    (0.47)
    0.2
    (0.47)
    -0.5
    (0.47)
    12 hours postdose
    -1.4
    (0.38)
    0.0
    (0.54)
    0.0
    (0.54)
    -0.3
    (0.47)
    -0.3
    (0.54)
    0.5
    (0.54)
    0.5
    (0.54)
    24 hours postdose
    -0.7
    (0.39)
    0.1
    (0.55)
    0.1
    (0.55)
    0.4
    (0.48)
    -0.1
    (0.55)
    0.0
    (0.55)
    -0.7
    (0.64)
    45. Secondary Outcome
    Title Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval
    Description Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF in the S-648414 group minus adjusted mean ΔQTcF in the placebo group at each time point.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 8 8 8 6 6 6
    0.5 hours postdose
    0.0
    (1.98)
    -2.4
    (1.99)
    -1.6
    (1.81)
    -0.9
    (1.98)
    -2.4
    (2.10)
    5.2
    (2.00)
    1 hour postdose
    1.7
    (2.04)
    -0.2
    (2.06)
    -1.0
    (1.87)
    1.2
    (2.04)
    1.1
    (2.16)
    7.0
    (2.07)
    1.5 hours postdose
    -0.1
    (2.40)
    -1.5
    (2.41)
    0.0
    (2.20)
    3.0
    (2.40)
    4.2
    (2.50)
    6.0
    (2.42)
    2 hours postdose
    -2.0
    (2.37)
    -0.9
    (2.38)
    -1.8
    (2.16)
    -1.1
    (2.36)
    2.5
    (2.46)
    6.4
    (2.39)
    2.5 hours postdose
    0.8
    (2.38)
    1.0
    (2.39)
    1.4
    (2.18)
    2.8
    (2.38)
    5.0
    (2.48)
    10.4
    (2.40)
    3 hours postdose
    4.1
    (2.13)
    0.5
    (2.14)
    1.2
    (1.94)
    4.5
    (2.12)
    1.4
    (2.24)
    12.0
    (2.15)
    4 hours postdose
    2.1
    (2.65)
    1.7
    (2.66)
    2.4
    (2.42)
    2.5
    (2.65)
    5.9
    (2.74)
    14.3
    (2.67)
    6 hours postdose
    -6.7
    (4.36)
    3.0
    (4.36)
    4.0
    (3.98)
    0.7
    (4.36)
    0.6
    (4.41)
    8.1
    (4.37)
    8 hours postdose
    -2.7
    (2.95)
    3.7
    (2.96)
    0.9
    (2.70)
    -1.8
    (2.95)
    0.7
    (3.03)
    9.1
    (2.97)
    12 hours postdose
    -1.0
    (4.21)
    1.8
    (4.22)
    1.8
    (3.85)
    -0.5
    (4.21)
    -2.1
    (4.27)
    9.6
    (4.23)
    24 hours postdose
    -3.6
    (2.04)
    0.2
    (2.05)
    -0.7
    (1.86)
    0.5
    (2.03)
    -0.4
    (2.15)
    8.8
    (2.36)
    46. Secondary Outcome
    Title Part 1: Placebo-corrected Change From Baseline in Heart Rate
    Description Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate. Placebo-corrected ΔHR (ΔΔHR) was calculated as the adjusted mean ΔHR in the S-648414 group minus adjusted mean ΔHR in the placebo group at each time point.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 6 6 6
    0.5 hours postdose
    -1.1
    (1.93)
    -2.3
    (1.95)
    -2.0
    (1.76)
    -1.0
    (1.92)
    -1.6
    (1.93)
    -2.5
    (1.92)
    1 hour postdose
    -4.2
    (2.00)
    -3.4
    (2.03)
    -3.5
    (1.83)
    -1.1
    (2.00)
    -2.5
    (2.00)
    -2.2
    (2.00)
    1.5 hours postdose
    -2.6
    (2.04)
    0.1
    (2.07)
    -2.6
    (1.86)
    0.0
    (2.04)
    0.6
    (2.04)
    0.0
    (2.04)
    2 hours postdose
    -2.7
    (2.26)
    -2.0
    (2.28)
    -2.1
    (2.06)
    -1.3
    (2.26)
    0.9
    (2.26)
    0.1
    (2.26)
    2.5 hours postdose
    -2.0
    (2.22)
    -3.8
    (2.25)
    -3.0
    (2.03)
    -1.5
    (2.22)
    2.0
    (2.22)
    -1.5
    (2.22)
    3 hours postdose
    -2.1
    (2.39)
    -0.7
    (2.41)
    -1.2
    (2.18)
    -0.8
    (2.39)
    2.9
    (2.39)
    0.4
    (2.39)
    4 hours postdose
    -1.4
    (2.45)
    0.4
    (2.47)
    -3.1
    (2.23)
    0.6
    (2.45)
    1.9
    (2.45)
    3.1
    (2.45)
    6 hours postdose
    -0.6
    (2.05)
    -2.8
    (2.07)
    -1.0
    (1.87)
    -1.5
    (2.05)
    2.0
    (2.05)
    2.3
    (2.05)
    8 hours postdose
    0.1
    (2.70)
    -0.9
    (2.72)
    -1.7
    (2.46)
    0.3
    (2.70)
    3.1
    (2.70)
    2.0
    (2.70)
    12 hours postdose
    -1.6
    (3.12)
    -0.7
    (3.14)
    -1.5
    (2.85)
    -0.3
    (3.12)
    6.4
    (3.12)
    0.7
    (3.12)
    24 hours postdose
    -2.2
    (2.85)
    -0.9
    (2.87)
    -1.9
    (2.60)
    0.4
    (2.85)
    -0.1
    (2.85)
    2.9
    (3.06)
    47. Secondary Outcome
    Title Part 1: Placebo-corrected Change From Baseline in PR Interval
    Description Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR interval in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate. Placebo-corrected ΔPR (ΔΔPR) was calculated as the adjusted mean ΔPR in the S-648414 group minus adjusted mean ΔPR in the placebo group at each time point.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 6 6 6
    0.5 hours postdose
    0.6
    (2.28)
    1.8
    (2.24)
    -0.5
    (2.06)
    0.9
    (2.25)
    -4.3
    (2.25)
    -0.4
    (2.24)
    1 hour postdose
    0.2
    (2.27)
    3.2
    (2.23)
    0.5
    (2.05)
    1.0
    (2.24)
    -7.2
    (2.23)
    0.2
    (2.23)
    1.5 hours postdose
    3.0
    (3.04)
    0.6
    (3.02)
    0.5
    (2.76)
    1.8
    (3.02)
    0.4
    (3.02)
    0.5
    (3.02)
    2 hours postdose
    2.0
    (2.52)
    2.6
    (2.49)
    -3.1
    (2.29)
    -2.2
    (2.50)
    -2.9
    (2.49)
    -0.6
    (2.49)
    2.5 hours postdose
    0.4
    (2.79)
    3.8
    (2.77)
    -0.8
    (2.54)
    -0.2
    (2.78)
    -5.9
    (2.77)
    -1.6
    (2.77)
    3 hours postdose
    3.8
    (3.25)
    3.8
    (3.23)
    1.8
    (2.96)
    -1.4
    (3.24)
    -5.2
    (3.23)
    -0.5
    (3.23)
    4 hours postdose
    2.5
    (2.91)
    2.7
    (2.89)
    -1.5
    (2.65)
    -0.5
    (2.90)
    -7.4
    (2.89)
    -2.2
    (2.89)
    6 hours postdose
    1.2
    (2.74)
    3.5
    (2.71)
    0.5
    (2.48)
    1.9
    (2.72)
    -4.1
    (2.71)
    -0.1
    (2.71)
    8 hours postdose
    1.4
    (3.31)
    6.8
    (3.28)
    -1.3
    (3.01)
    -2.6
    (3.29)
    -2.6
    (3.29)
    1.4
    (3.29)
    12 hours postdose
    1.3
    (3.70)
    4.5
    (3.68)
    -0.4
    (3.37)
    -0.1
    (3.69)
    -6.9
    (3.68)
    0.4
    (3.68)
    24 hours postdose
    1.6
    (2.82)
    2.2
    (2.79)
    2.0
    (2.56)
    -2.7
    (2.80)
    -0.7
    (2.80)
    -1.6
    (2.99)
    48. Secondary Outcome
    Title Part 1: Placebo-corrected Change From Baseline in QRS Duration
    Description Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS duration in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in QRS duration (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate. Placebo-corrected ΔQRS (ΔΔQRS) was calculated as the adjusted mean ΔQRS in the S-648414 group minus adjusted mean ΔQRS in the placebo group at each time point.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.
    Arm/Group Title Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 6 6 8 6 6 6
    0.5 hours postdose
    0.2
    (0.37)
    -0.1
    (0.37)
    0.5
    (0.34)
    0.2
    (0.37)
    0.4
    (0.37)
    0.2
    (0.37)
    1 hour postdose
    0.3
    (0.39)
    0.5
    (0.39)
    0.6
    (0.35)
    0.7
    (0.39)
    0.6
    (0.39)
    0.8
    (0.39)
    1.5 hours postdose
    -0.7
    (0.77)
    -0.6
    (0.77)
    -0.1
    (0.71)
    -0.1
    (0.77)
    -0.3
    (0.77)
    0.0
    (0.77)
    2 hours postdose
    0.5
    (0.42)
    0.4
    (0.42)
    1.1
    (0.38)
    0.5
    (0.42)
    0.7
    (0.42)
    1.1
    (0.42)
    2.5 hours postdose
    0.1
    (0.42)
    0.3
    (0.42)
    -0.1
    (0.38)
    0.3
    (0.42)
    0.1
    (0.42)
    0.4
    (0.42)
    3 hours postdose
    0.2
    (0.38)
    0.4
    (0.38)
    0.3
    (0.35)
    0.5
    (0.38)
    0.5
    (0.38)
    0.3
    (0.38)
    4 hours postdose
    -0.3
    (0.50)
    0.0
    (0.50)
    0.3
    (0.46)
    0.1
    (0.50)
    0.8
    (0.50)
    0.8
    (0.50)
    6 hours postdose
    -0.3
    (0.95)
    0.0
    (0.95)
    -0.2
    (0.87)
    -0.8
    (0.95)
    1.1
    (0.95)
    1.3
    (0.95)
    8 hours postdose
    0.2
    (0.58)
    0.7
    (0.58)
    0.5
    (0.53)
    0.5
    (0.58)
    1.1
    (0.58)
    0.3
    (0.58)
    12 hours postdose
    1.4
    (0.66)
    1.4
    (0.66)
    1.1
    (0.60)
    1.1
    (0.66)
    1.9
    (0.66)
    1.9
    (0.66)
    24 hours postdose
    0.8
    (0.68)
    0.8
    (0.67)
    1.1
    (0.62)
    0.6
    (0.68)
    0.7
    (0.67)
    0.0
    (0.75)
    49. Secondary Outcome
    Title Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS
    Description A participant was determined as an outlier if the following criteria (assessed separately) were met for the ECG intervals at any time point: QTcF: Treatment-emergent value of > 450 and ≤ 480 ms when not present at Baseline (new onset) Treatment-emergent value of > 480 and ≤ 500 ms when not present at Baseline (new onset) Treatment-emergent value of > 500 ms when not present at Baseline (new onset) Increase of QTcF (ΔQTcF) from Baseline of > 30 and ≤ 60 ms Increase of QTcF from Baseline > 60 ms HR: Decrease of HR from Baseline > 25% resulting in HR < 50 bpm Increase of HR from Baseline > 25% resulting in HR > 100 bpm PR: Increase of PR from Baseline > 25% resulting in PR > 200 ms QRS: Increase of QRS from Baseline > 25% resulting in QRS > 120 ms
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    QT/QTc population
    Arm/Group Title Part 1: Placebo Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of matching placebo in a fasted state on Day 1. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 12 6 6 8 6 6 6
    QTcF > 450 and ≤ 480 ms
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    QTcF > 480 and ≤ 500 ms
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    QTcF > 500 ms
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    ΔQTcF > 30 and ≤ 60 ms
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    ΔQTcF > 60 ms
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    HR < 50 (bpm) with a decrease in ΔHR > 25%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    HR > 100 (bpm) with an increase in ΔHR > 25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    PR > 200 (ms) with an increase in ΔPR > 25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    QRS > 120 (ms) with an increase in ΔQRS > 25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    50. Secondary Outcome
    Title Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence
    Description T-wave abnormalities were categorized as follows: 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
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    QT/QTc population)
    Arm/Group Title Part 1: Placebo Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414
    Arm/Group Description Participants received a single oral dose of matching placebo in a fasted state on Day 1. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1.
    Measure Participants 12 6 6 8 6 6 6
    Flat
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Notched (+)
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Biphasic
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Normal (-)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Notched (-)
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    U-Wave presence
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Adverse Events

    Time Frame Part 1: From dosing on Day 1 or Day 14 up to 10 days post dose; Part 2: From the first dose up to 10 days after end of dosing (25 days); Part 3: From the first dose up to Day 36. A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment.
    Adverse Event Reporting Description
    Arm/Group Title Part 1: Placebo - Fasted Part 1: Placebo - Fed Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414 Part 2: Midazolam (Day -2) Part 2: Placebo (Days 1-13) Part 2: 50 mg S-648414 (Days 1-13) Part 2: 30 mg S-648414 (Days 1-13) Part 2: Placebo + Midazolam (Day 14) Part 2: 50 mg S-648414 + Midazolam (Day 14) Part 2: 30 mg S-648414 + Midazolam (Day 14) Part 3: Group I Dolutegravir Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Arm/Group Description Participants received a single oral dose of matching placebo in a fasted state on Day 1. Participants received a single dose of matching placebo in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 100 mg S-648414 in a fed state (after a high-fat meal) on Day 14. Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1. Participants received a single oral dose of 5 mg midazolam on Day -2 Participants received matching placebo to S-648414 once a day on Days 1 to 13. Participants received 50 mg S-648414 once a day on Days 1 to 13. Participants received 30 mg S-648414 once a day on Days 1 to 13. Participants received matching placebo to S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants received 50 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants received 30 mg S-648414 and a single oral dose of 5 mg midazolam on Day 14. Participants received 50 mg dolutegravir orally once a day on Days 1 to 7. Participants received 100 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. Participants received 50 mg dolutegravir once a day on Days 1 to 7. Participants received 200 mg S-648414 orally once a day on Days 15 to 21. Participants received 50 mg dolutegravir once a day co-administered with 200 mg S-648414 orally once a day on Days 22 to 28.
    All Cause Mortality
    Part 1: Placebo - Fasted Part 1: Placebo - Fed Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414 Part 2: Midazolam (Day -2) Part 2: Placebo (Days 1-13) Part 2: 50 mg S-648414 (Days 1-13) Part 2: 30 mg S-648414 (Days 1-13) Part 2: Placebo + Midazolam (Day 14) Part 2: 50 mg S-648414 + Midazolam (Day 14) Part 2: 30 mg S-648414 + Midazolam (Day 14) Part 3: Group I Dolutegravir Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Serious Adverse Events
    Part 1: Placebo - Fasted Part 1: Placebo - Fed Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414 Part 2: Midazolam (Day -2) Part 2: Placebo (Days 1-13) Part 2: 50 mg S-648414 (Days 1-13) Part 2: 30 mg S-648414 (Days 1-13) Part 2: Placebo + Midazolam (Day 14) Part 2: 50 mg S-648414 + Midazolam (Day 14) Part 2: 30 mg S-648414 + Midazolam (Day 14) Part 3: Group I Dolutegravir Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Other (Not Including Serious) Adverse Events
    Part 1: Placebo - Fasted Part 1: Placebo - Fed Part 1: 10 mg S-648414 Part 1: 30 mg S-648414 Part 1: 100 mg S-648414 Fasted Part 1: 100 mg S-648414 Fed Part 1: 250 mg S-648414 Part 1: 500 mg S-648414 Part 1: 1000 mg S-648414 Part 2: Midazolam (Day -2) Part 2: Placebo (Days 1-13) Part 2: 50 mg S-648414 (Days 1-13) Part 2: 30 mg S-648414 (Days 1-13) Part 2: Placebo + Midazolam (Day 14) Part 2: 50 mg S-648414 + Midazolam (Day 14) Part 2: 30 mg S-648414 + Midazolam (Day 14) Part 3: Group I Dolutegravir Part 3: 100 mg S-648414 Part 3: 100 mg S-648414 + Dolutegravir Part 3: Dolutegravir Part 3: 200 mg S-648414 Part 3: 200 mg S-648414 + Dolutegravir
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/12 (16.7%) 0/2 (0%) 0/6 (0%) 1/6 (16.7%) 2/8 (25%) 2/8 (25%) 1/6 (16.7%) 1/6 (16.7%) 2/6 (33.3%) 0/20 (0%) 2/4 (50%) 2/8 (25%) 3/8 (37.5%) 0/2 (0%) 1/7 (14.3%) 1/8 (12.5%) 3/14 (21.4%) 3/14 (21.4%) 4/14 (28.6%) 2/14 (14.3%) 5/14 (35.7%) 2/14 (14.3%)
    Eye disorders
    Abnormal sensation in eye 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 1/8 (12.5%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Dry eye 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 1/8 (12.5%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 2/14 (14.3%) 0/14 (0%)
    Eye pain 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 1/8 (12.5%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Iritis 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 1/4 (25%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Vision blurred 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Gastrointestinal disorders
    Nausea 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 1/8 (12.5%) 1/8 (12.5%) 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Abdominal discomfort 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Abdominal distension 1/12 (8.3%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Aphthous ulcer 1/12 (8.3%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Diarrhoea 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 1/14 (7.1%)
    Vomiting 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 1/8 (12.5%) 1/8 (12.5%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Abnormal faeces 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Constipation 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 2/14 (14.3%) 1/14 (7.1%) 0/14 (0%)
    Abdominal pain lower 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 1/14 (7.1%)
    Abdominal pain upper 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 1/14 (7.1%)
    Immune system disorders
    Drug hypersensitivity 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 1/4 (25%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Infections and infestations
    Upper respiratory tract infection 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 1/8 (12.5%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Injury, poisoning and procedural complications
    Arthropod bite 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Investigations
    Blood creatine phosphokinase increased 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 1/8 (12.5%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 1/14 (7.1%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    C-reactive protein increased 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 1/8 (12.5%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Intraocular pressure increased 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 1/14 (7.1%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Musculoskeletal and connective tissue disorders
    Neck pain 0/12 (0%) 0/2 (0%) 0/6 (0%) 1/6 (16.7%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Musculoskeletal chest pain 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 1/7 (14.3%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Myalgia 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Temporomandibular joint syndrome 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Back pain 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 2/14 (14.3%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Nervous system disorders
    Headache 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 1/8 (12.5%) 1/8 (12.5%) 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 1/8 (12.5%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 1/14 (7.1%) 3/14 (21.4%) 2/14 (14.3%) 0/14 (0%) 1/14 (7.1%) 1/14 (7.1%)
    Dizziness 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 1/8 (12.5%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Head discomfort 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 1/14 (7.1%) 0/14 (0%)
    Psychiatric disorders
    Anxiety 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Renal and urinary disorders
    Chromaturia 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 1/7 (14.3%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Micturition disorder 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 1/7 (14.3%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Urine odour abnormal 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Respiratory, thoracic and mediastinal disorders
    Allergic cough 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Rhinitis allergic 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 1/8 (12.5%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Skin and subcutaneous tissue disorders
    Hyperhidrosis 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Pruritus 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Dry skin 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 2/8 (25%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Urticaria 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 1/8 (12.5%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%)
    Rash 0/12 (0%) 0/2 (0%) 0/6 (0%) 0/6 (0%) 0/8 (0%) 0/8 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/20 (0%) 0/4 (0%) 0/8 (0%) 0/8 (0%) 0/2 (0%) 0/7 (0%) 0/8 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 0/14 (0%) 1/14 (7.1%) 0/14 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.

    Results Point of Contact

    Name/Title Shionogi Clinical Trials Administrator
    Organization Shionogi Inc.
    Phone 800-849-9707
    Email shionogiclintrials-admin@shionogi.co.jp
    Responsible Party:
    Shionogi
    ClinicalTrials.gov Identifier:
    NCT04147715
    Other Study ID Numbers:
    • 1908T0911
    First Posted:
    Nov 1, 2019
    Last Update Posted:
    Nov 1, 2021
    Last Verified:
    Oct 1, 2021