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

NCT04147715 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 1908T0911
• Study Type: interventional
• Target: 98
• Locations: 2 countries
• Sites: 2

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.

Conditions

Healthy Volunteer

Keywords

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

Outcome Measures

Primary Outcomes (13)

• Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  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.

  From dosing on Day 1 or Day 14 up to 10 days post dose

• Part 2: Number of Participants With Treatment-emergent Adverse Events

  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.

  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.

• Part 3: Number of Participants With Treatment-emergent Adverse Events

  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.

  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.

• Part 3: Maximum Plasma Concentration (Cmax) of S-648414

  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).

  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.

• Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414

  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).

  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.

• Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ)

  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).

  Day 22 and Day 29 (24 hours post-dosing on Days 21 and 28)

• Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414

  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.

  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.

• Part 3: Apparent Total Clearance (CL/F) of S-648414

  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

  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.

• Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir

  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.

  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.

• Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir

  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.

  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.

• Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ)

  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.

  Day 8 and Day 29 (24 hours post-dosing on Day 7 and Day 28).

• Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir

  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.

  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.

• Part 3: Apparent Total Clearance (CL/F) of Dolutegravir

  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

  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 (37)

• 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.

• 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.

• 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.

• 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.

• 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.

Study Arms (12)

Part 1: Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Part 1: 10 mg S-648414

EXPERIMENTAL

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

Drug: S-648414

Part 1: 30 mg S-648414

EXPERIMENTAL

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

Drug: S-648414

Part 1: 100 mg S-648414

EXPERIMENTAL

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

Part 1: 250 mg S-648414

EXPERIMENTAL

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

Drug: S-648414

Part 1: 500 mg S-648414

EXPERIMENTAL

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

Drug: S-648414

Part 1: 1000 mg S-648414

EXPERIMENTAL

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

Drug: S-648414

Part 2: Placebo + Midazolam

PLACEBO COMPARATOR

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; Drug: Midazolam

Part 2: 50 mg S-648414 + Midazolam

EXPERIMENTAL

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; Drug: Midazolam

Part 2: 30 mg S-648414 + Midazolam

EXPERIMENTAL

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; Drug: Midazolam

Part 3: 100 mg S-648414 + Dolutegravir

EXPERIMENTAL

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; Drug: Dolutegravir

Part 3: 200 mg S-648414 + Dolutegravir

EXPERIMENTAL

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; Drug: Dolutegravir

Interventions

S-648414 DRUG

Tablet for oral administration

Part 1: 10 mg S-648414; Part 1: 100 mg S-648414; Part 1: 1000 mg S-648414; Part 1: 250 mg S-648414; Part 1: 30 mg S-648414; Part 1: 500 mg S-648414; Part 2: 30 mg S-648414 + Midazolam; Part 2: 50 mg S-648414 + Midazolam; Part 3: 100 mg S-648414 + Dolutegravir; Part 3: 200 mg S-648414 + Dolutegravir

Placebo DRUG

Tablet for oral administration

Part 1: Placebo; Part 2: Placebo + Midazolam

Midazolam DRUG

Solution for oral administration

Also known as: Versed

Part 2: 30 mg S-648414 + Midazolam; Part 2: 50 mg S-648414 + Midazolam; Part 2: Placebo + Midazolam

Dolutegravir DRUG

Tablet for oral administration

Also known as: TIVICAY

Part 3: 100 mg S-648414 + Dolutegravir; Part 3: 200 mg S-648414 + Dolutegravir

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• Capable of giving signed informed consent
• Body mass index (BMI) ≥ 18.5 to \< 32.0 kg/m² at the Screening visit．
• 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.
• 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.
• 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.

You may not qualify if:

• 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.
• History or presence of cancer in last 5 years except for non-melanoma skin cancers.
• Risk factors for:
• Torsades de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT Syndrome or Brugada Syndrome)
• 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
• 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).
• History of hypersensitivity or severe side effects induced by a drug.
• Any condition requiring medication and/or other treatment, such as dietary restriction and physical therapy.
• 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).
• 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.
• 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.
• 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).
• 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).
• 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 \[25 mL/1 oz.\]).
• A positive drug or alcohol screen at the Screening visit or upon admission to the CRU.

Sponsors & Collaborators

• Shionogi: lead

Study Sites (2)

PPD Ph 1 Clinical Research Unit

Austin, Texas, 78744, United States

Location

P-One Clinic

Hachiōji, Toyko, 192-0071, Japan

Location

MeSH Terms

Interventions

Midazolam; dolutegravir

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Shionogi Clinical Trials Administrator
• Organization: Shionogi Inc.

shionogiclintrials-admin@shionogi.co.jp

800-849-9707

Study Officials

• Shionogi Clinical Trials Administrator Clinical Support Help Line

  Shionogi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Parts 1 and 2 were blinded studies. Part 3 was an open-label study and, therefore, did not include blinding.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2019
• First Posted: November 1, 2019
• Study Start: October 9, 2019
• Primary Completion: September 22, 2020
• Study Completion: September 29, 2020
• Last Updated: November 1, 2021
• Results First Posted: October 20, 2021

Record last verified: 2021-10

Locations

JP (1); US (1)