Evaluation of Safety, Tolerability, Pharmacokinetics, Drug-Drug and Food Interactions of Single and Multiple Doses of S-648414 in Healthy Adults
Condition: Healthy Volunteer
Intervention: S-648414; Placebo; Midazolam; Dolutegravir
Intervention description: Tablet for oral administration; Tablet for oral administration; Solution for oral administration; Tablet for oral administration
Intervention MeSH terms: Dolutegravir; Midazolam
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
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.
Enrollment: 98.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Pharmacokinetics; S-648414; Food effect; Antiretroviral; Drug-drug interaction

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.
    

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.