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

NCT ID: NCT04147715

Last Updated: 2021-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 98 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-09
• Study Completion Date: 2020-09-29

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)"

Conditions

Healthy Volunteer

Keywords

Pharmacokinetics; S-648414; Food effect; Antiretroviral; Drug-drug interaction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Part 1: 1000 mg S-648414

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

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

Part 1: Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Tablet for oral administration

Part 1: 10 mg S-648414

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

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

Part 1: 30 mg S-648414

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

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

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.

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

Part 1: 250 mg S-648414

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

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

Part 1: 500 mg S-648414

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

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Tablet for oral administration

Midazolam

Intervention Type: DRUG

Solution for oral administration

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.

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

Midazolam

Intervention Type: DRUG

Solution for oral administration

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.

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

Midazolam

Intervention Type: DRUG

Solution for oral administration

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.

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

Dolutegravir

Intervention Type: DRUG

Tablet for oral administration

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.

Group Type: EXPERIMENTAL

S-648414

Intervention Type: DRUG

Tablet for oral administration

Dolutegravir

Intervention Type: DRUG

Tablet for oral administration

Interventions

S-648414

Tablet for oral administration

Intervention Type: DRUG

Placebo

Tablet for oral administration

Intervention Type: DRUG

Midazolam

Solution for oral administration

Intervention Type: DRUG

Dolutegravir

Tablet for oral administration

Intervention Type: DRUG

Other Intervention Names

Versed; TIVICAY

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Shionogi

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Shionogi Clinical Trials Administrator Clinical Support Help Line

Role: STUDY_DIRECTOR

Shionogi

Locations

PPD Ph 1 Clinical Research Unit

Austin, Texas, United States

P-One Clinic

Hachiōji, Toyko, Japan

Countries

United States; Japan

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

1908T0911

Identifier Type: -

Identifier Source: org_study_id