A Study to Investigate the Effect of Esomeprazole and the Effect of Food on the Pharmacokinetics of Balovaptan in Healthy Volunteers

Overview

This study will investigate the effect of food and the effect of esomeprazole on the pharmacokinetics (PK) of a single dose of balovaptan in healthy volunteers.

Full Title of Study: “A Single-Center, Part-Randomized, Open-Label, Single-Dose, Three-Period, Crossover Study to Investigate the Effect of Esomeprazole and The Effect of Food on the Pharmacokinetics of Balovaptan in Healthy Volunteers”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 21, 2019

Interventions

  • Drug: Balovaptan
    • Balovaptan will be administered after a high-fat, high-calorie meal (Treatment A), after a 10-hour fast (Treatment B), and after a 10-hour fast with esomeprazole 40 mg (Treatment C)
  • Drug: Esomeprazole
    • Esomeprazole will be administered once daily for 6 days and with a single dose of balovaptan 1 hour after the fifth esomeprazole dose

Arms, Groups and Cohorts

  • Experimental: Treatment sequence ABC
    • In Period 1 participants will receive 1 tablet of balovaptan after high-fat, high-calorie meal. In Period 2, after 12 to 21 days wash-out, participants will receive 1 tablet of balovaptan after 10-hour fast. In Period 3 participants will receive esomeprazole administered once daily for 6 days and with a single oral dose of balovaptan in the fasted state 1 hour after the fifth esomeprazole dose
  • Experimental: Treatment sequence BAC
    • In Period 1 participants will receive 1 tablet of balovaptan after 10-hour fast. In Period 2, after 12 to 21 days wash-out, participants will receive 1 tablet of balovaptan after high-fat, high-calorie meal. In Period 3 participants will receive esomeprazole administered once daily for 6 days and with a single oral dose of balovaptan in the fasted state 1 hour after the fifth esomeprazole dose

Clinical Trial Outcome Measures

Primary Measures

  • Maximum Plasma Concentration (Cmax) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Area Under the Concentration-Time Curve from Time Extrapolated to Infinity (AUC (0-inf)) of balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Area Under the Concentration-Time Curve from Time 0 to 24 hours (AUC(0-24h)) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16 and 24 hours post dose
  • Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Time to Reach Cmax in Plasma (Tmax) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Last Quantifiable Concentration (Clast) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Time To the Last Quantifiable Concentration (Tlast) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Time Between Dosing and Time of First Balovaptan Plasma Concentration (Tlag)
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Apparent Clearance (Cl/F) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Apparent Volume of Distribution (Vd/F) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Terminal Elimination Phase Half-Life (T1/2) of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Plasma Concentrations of Balovaptan
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose

Secondary Measures

  • Maximum Plasma Concentration (Cmax) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Maximum Plasma Concentration (Cmax) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Maximum Plasma Concentration (Cmax) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Area Under the Concentration-Time Curve from Time Extrapolated to Infinity (AUC (0-inf)) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Area Under the Concentration-Time Curve from Time Extrapolated to Infinity (AUC (0-inf)) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Area Under the Concentration-Time Curve from Time Extrapolated to Infinity (AUC (0-inf)) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Area Under the Concentration-Time Curve from Time 0 to 24 hours (AUC(0-24h)) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16 and 24 hours post dose
  • Area Under the Concentration-Time Curve from Time 0 to 24 hours (AUC(0-24h)) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16 and 24 hours post dose
  • Area Under the Concentration-Time Curve from Time 0 to 24 hours (AUC(0-24h)) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Time to Reach Cmax in Plasma (Tmax) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Time to Reach Cmax in Plasma (Tmax) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Time to Reach Cmax in Plasma (Tmax) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Last Quantifiable Concentration (Clast) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Last Quantifiable Concentration (Clast) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Last Quantifiable Concentration (Clast) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Time To the Last Quantifiable Concentration (Tlast) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Time To the Last Quantifiable Concentration (Tlast) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Time To the Last Quantifiable Concentration (Tlast) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Apparent Clearance (Cl/F) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Apparent Clearance (Cl/F) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Apparent Clearance (Cl/F) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Apparent Volume of Distribution (Vd/F) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Apparent Volume of Distribution (Vd/F) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Apparent Volume of Distribution (Vd/F) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Terminal Elimination Phase Half-Life (T1/2) of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Terminal Elimination Phase Half-Life (T1/2) of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Terminal Elimination Phase Half-Life (T1/2) of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose
  • Percentage of Patricipants with Adverse Events (AEs)
    • Time Frame: Randomization to end of study (up to approximately 11 weeks)
  • Plasma Concentration of M2 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Plasma Concentration of M3 Metabolite
    • Time Frame: Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
  • Plasma Concentrations of Esomeprazole
    • Time Frame: Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose

Participating in This Clinical Trial

Inclusion Criteria

  • No evidence of any active or chronic disease
  • Body mass index (BMI) between 18 and 32 kg/m2 inclusive, at screening
  • For women of childbearing potential: if engaging in heterosexual activity, agreement to use at least two adequate forms of contraception during the entire study and for 90 days following the last dose of study drug
  • For men: agreement to use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria

  • Pregnancy or lactation (positive serum pregnancy test at screening or at admission)
  • Any condition or disease detected during the medical interview/physical examination that would render the subject unsuitable for the study, place the subject at undue risk or interfere with the ability of the subject to complete the study in the opinion of the Investigator
  • In the opinion of the Investigator, any major illness within 4 weeks prior to the screening examination or any febrile illness within 1 week prior to screening.
  • History of any clinically significant, as determined by the investigator, gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, cardiovascular, endocrinological, hematological, lymphatic, musculoskeletal, genitourinary, immunological, dermatological, or connective tissue or allergic disease, metabolic disorder, or cancer
  • Signs and symptoms potentially indicative of peripheral neuropathy
  • History or evidence of any medical condition potentially altering the absorption, distribution, metabolism, or elimination of drugs
  • A history of clinically significant in the opinion of the Investigator hypersensitivity
  • History or presence of clinically significant ECG abnormalities before study drug administration
  • Clinically significant abnormalities in laboratory test results
  • History of coagulopathies, bleeding disorders, or blood dyscrasias
  • Current suicidal risk, in the opinion of the Investigator
  • Unexplained syncope during the 6 months prior to screening or with presyncopal and/or syncopal symptoms during orthostatic challenge testing
  • Current smoker or user of tobacco or nicotine-containing products or subjects who have smoked or used tobacco or nicotine-containing products within 3 months prior to first study drug administration
  • Suspicion of or presence of a clinically relevant history of or current alcohol and/or other substance abuse or addiction.
  • Alcohol consumption of >14 units per week for males and females
  • Positive urine alcohol test or urine drug screen at screening or Day -1 of any treatment period
  • Hormone replacement therapy if postmenopausal status cannot be ascertained from medical history or FSH levels
  • Clinically relevant deviation from normal in the physical examination including vital signs, as determined by the investigator
  • Positive result for HIV 1, HIV 2, hepatitis C virus antibody, or hepatitis B core (HBc) antibody.
  • Participation in an investigational drug or device study within 4 weeks or 5 times the elimination half-life, whichever is longer, prior to first dosing, or within 5 months prior to first administration of study drug in case of a study with a biological, as calculated from the day of Follow-up visit from the previous study
  • Donation of blood or plasma or significant blood loss within 3 months prior to screening
  • Dietary restrictions that would prohibit the consumption of standardized meals or the highfat, high-calorie meal planned for this study
  • Use of any prohibited medications or food before study start or subjects who do not agree to refrain from consuming prohibited medications or food during the study
  • Conditions requiring concomitant medication during the study (including for dental conditions).
  • Any prescribed systemic or topical medication within 4 weeks (or within 5 times the elimination half-life of the medication, whichever is longer) of the first administration of study drug
  • Used any nonprescribed systemic or topical medication or herbal remedies within 7 days before the first study drug administration
  • Received any medications known to chronically alter drug absorption or elimination processes within 4 weeks before the first administration of study drug
  • Use of any drugs or substances, including herbal treatments such as St John's wort, that are known to be substrates, inducers, or inhibitors of CYP3A4 within 4 weeks before the first administration of study drug
  • Use of any drugs or substances, including herbal treatments, such as fluoxetine, fluvoxamine, aspirin, norethisterone, rifampicin, etc that are known to be substrates, inducers, or inhibitors of CYP2C19 within 4 weeks before the first administration of study drug
  • Subjects under judicial supervision, guardianship, or curatorship
  • Poor venous access for blood sampling
  • Participants who are intolerant to sucrose
  • Previous exposure to balovaptan

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Hoffmann-La Roche
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Clinical Trials, Study Director, Hoffmann-La Roche
  • Overall Contact(s)
    • Reference Study ID Number: WP41047 www.roche.com/about_roche/roche_worldwide.htm, 888-662-6728 (U.S. and Canada), global-roche-genentech-trials@gene.com

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