Clinical trial NCT04147715: Evaluation of Safety, Tolerability, Pharmacokinetics, Drug-Drug and Food Interactions of Single and Multiple Doses of S-648414 in Healthy Adults
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteer
Keywords: Pharmacokinetics
S-648414
Food effect
Antiretroviral
Drug-drug interaction
Lead sponsor: Shionogi Inc.
Sponsor class: INDUSTRY
First posted: 2019-11-01
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

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

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

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

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

Eligibility criteria: 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).

   a) Specific to Japan sites: enrollment in Part 3 (Group I and J) will consist of only White or Black or African American race.
2. Capable of giving signed informed consent
3. Body mass index (BMI) ≥ 18.5 to \< 32.0 kg/m² at the Screening visit．
4. Considered medically healthy as determined by the investigator or subinvestigator (suitably qualified), based on medical history and clinical evaluations including physical examination, clinical laboratory tests, vital sign measurements, and 12-lead electrocardiogram (ECG) at Screening and at upon admission to the Clinical Research Unit (CRU) and prior to administration of study intervention on Day 1.
5. 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.
6. 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:

   1. Torsades de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT Syndrome or Brugada Syndrome)
   2. Unexplained syncope, sick sinus syndrome, second- or third-degree atrioventricular (AV) block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, angina, prolonged QT interval, or conduction abnormalities
4. History of GI surgery or disease including, but not limited to, gastric band/gastric resection and/or intestinal resection and/or duodenal disease (ie, celiac disease) that may result in clinically significant malabsorption (except for an appendectomy).
5. History of hypersensitivity or severe side effects induced by a drug.
6. Any condition requiring medication and/or other treatment, such as dietary restriction and physical therapy.
7. History of significant multiple and/or severe allergic symptoms including food allergy (NOTE: Study participants with seasonal allergies may participate unless they have ongoing symptoms).
8. Used drugs or substances known to be inducers or inhibitors of cytochrome P450 enzymes and/or P-glycoprotein within 28 days prior to admission to the CRU.
9. Used prescription or over-the-counter (OTC) drugs, antacids, proton pump inhibitors, H2 antagonists, Chinese herbal medicines, oral cannabidiol, vitamins, minerals, herbal, and dietary supplements within 14 days prior to admission to the CRU.
10. Refuses to abstain from ingesting caffeine- or xanthine-containing products/medications (eg, coffee, tea, cola drinks, other caffeinated beverages, or chocolate) from 24 hours prior to admission to the CRU or refuses to refrain from consuming such products throughout the study (including Follow-up period).
11. Consumed alcohol or used alcohol-containing products within 72 hours prior to admission to the CRU or refuses to refrain from consuming such products throughout the study (including Follow-up period).
12. History of recreational drug use in the previous 6 months, or has a history of problematic alcohol use (defined as study participants who regularly consume excessive amounts of alcohol, defined as \> 3 glasses of alcoholic beverages per day (1 glass is approximately equivalent to: beer \[284 mL/10 ounces (oz.)\], wine \[125 mL/4 oz.\] or distilled spirits \[25 mL/1 oz.\]).
13. A positive drug or alcohol screen at the Screening visit or upon admission to the CRU.
14. Used tobacco- or nicotine-containing products (including cigarette, pipe, cigar, chewing, nicotine patch, 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).
15. Consumed grapefruit, grapefruit juice, Seville orange juice, orange juice, apple juice, vegetables from the mustard green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard greens), or charbroiled meats within 7 days prior to admission to the CRU or refuses to refrain from consuming such products throughout the study (including Follow-up period).
16. A corrected QT (QTc) interval of \> 450 msec for males and \> 470 msec for females (Fridericia's method) at the Screening visit or upon admission to the CRU.
17. Systolic blood pressure is outside the range of 90 to 140 mm Hg, diastolic blood pressure is outside the range of 50 to 90 mm Hg, or pulse rate is outside the range of 40 to 100 beats per minute (bpm) or considered ineligible by the investigator or subinvestigator at the Screening visit or upon admission to the CRU.
18. Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) values are greater than the upper limit of normal (ULN), or estimated glomerular filtration rate (eGFR) \< 90 mL/min/1.73 m² at Screening or upon admission to the CRU.
19. A positive serological test for untreated syphilis, positive hepatitis B surface antigen, positive hepatitis C virus antibody, or positive human immunodeficiency virus (HIV) antigen/antibody result at the Screening visit.
20. Participated in any other investigational trials or has been exposed to other investigational drugs within 28 days or 5 half-lives of the previously administered investigational drug (date derived from last study procedure \[blood collection or dosing\] of previous trial), whichever is longer, prior to admission to the CRU.
21. Previously received S-648414.
22. Poor venous access.
23. 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.
24. Considered inappropriate for participation in the study for any reason by the investigator or subinvestigator.

Primary outcomes:
measure: Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From dosing on Day 1 or Day 14 up to 10 days post dose
measure: Part 2: Number of Participants With Treatment-emergent Adverse Events
timeFrame: 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.
measure: Part 3: Number of Participants With Treatment-emergent Adverse Events
timeFrame: 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.
measure: Part 3: Maximum Plasma Concentration (Cmax) of S-648414
timeFrame: 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.
measure: Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414
timeFrame: 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.
measure: Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ)
timeFrame: Day 22 and Day 29 (24 hours post-dosing on Days 21 and 28)
measure: Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414
timeFrame: 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.
measure: Part 3: Apparent Total Clearance (CL/F) of S-648414
timeFrame: 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.
measure: Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir
timeFrame: 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.
measure: Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir
timeFrame: 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.
measure: Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ)
timeFrame: Day 8 and Day 29 (24 hours post-dosing on Day 7 and Day 28).
measure: Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir
timeFrame: 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.
measure: Part 3: Apparent Total Clearance (CL/F) of Dolutegravir
timeFrame: 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.
Secondary outcomes:
measure: Part 1: Maximum Plasma Concentration (Cmax) of S-648414
timeFrame: 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.
measure: Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414
timeFrame: 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.
measure: Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414
timeFrame: 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.
measure: Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414
timeFrame: 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.
measure: Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414
timeFrame: 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.
measure: Part 1: Terminal Elimination Rate Constant (λz) of S-648414
timeFrame: 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.
measure: Part 1: Mean Residence Time (MRT) of S-648414
timeFrame: 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.
measure: Part 1: Apparent Total Clearance (CL/F) of S-648414
timeFrame: 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.
measure: Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414
timeFrame: 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.
measure: Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96)
timeFrame: 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
measure: Part 1: Renal Clearance (CLR) of S-648414
timeFrame: 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
measure: Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration
timeFrame: 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.
measure: Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration
timeFrame: 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.
measure: Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration
timeFrame: 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.
measure: Part 2: Terminal Elimination Half-life (t1/2,z) of S-648414 Following Multiple-dose Administration
timeFrame: 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.
measure: Part 2: Terminal Elimination Rate Constant (λz) of S-648414 Following Multiple-dose Administration
timeFrame: 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.
measure: Part 2: Apparent Total Clearance (CL/F) of S-648414 Following Multiple-dose Administration
timeFrame: Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
measure: Part 2: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 Following Multiple-dose Administration
timeFrame: 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.
measure: Part 2: Fraction of S-648414 Dose Excreted in Urine Over the Dosing Interval (Feu0- τ) Following Multiple-dose Administration
timeFrame: Day 14 0-24 hours postdose
measure: Part 2: Renal Clearance (CLR) of S-648414 Following Multiple-dose Administration
timeFrame: Day 14 0-24 hours postdose
measure: Part 2: Maximum Plasma Concentration (Cmax) of Midazolam
timeFrame: 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.
measure: Part 2: Time to Maximum Plasma Concentration of Midazolam
timeFrame: 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.
measure: Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam
timeFrame: 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.
measure: Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam
timeFrame: 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.
measure: Part 2: Terminal Elimination Half-life for Midazolam
timeFrame: 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.
measure: Part 2: Terminal Elimination Rate Constant for Midazolam
timeFrame: 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.
measure: Part 2: Mean Residence Time for Midazolam
timeFrame: 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.
measure: Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF)
timeFrame: 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.
measure: Parts 1: Change From Baseline in Heart Rate (HR)
timeFrame: 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.
measure: Part 1: Change From Baseline in PR Interval
timeFrame: 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.
measure: Part 1: Change From Baseline in QRS Interval
timeFrame: 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.
measure: Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval
timeFrame: 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.
measure: Part 1: Placebo-corrected Change From Baseline in Heart Rate
timeFrame: 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.
measure: Part 1: Placebo-corrected Change From Baseline in PR Interval
timeFrame: 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.
measure: Part 1: Placebo-corrected Change From Baseline in QRS Duration
timeFrame: 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.
measure: Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS
timeFrame: 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.
measure: Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence
timeFrame: 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.
Other outcomes:
Locations:
city: Austin
country: United States
facility: PPD Ph 1 Clinical Research Unit
state: Texas
city: Hachioji City
country: Japan
facility: P-One Clinic
state: Toyko
Study officials:
affiliation: Shionogi
name: Shionogi Clinical Trials Administrator Clinical Support Help Line
role: STUDY_DIRECTOR
References: