The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of RO6889450 in Healthy Volunteers

Hoffmann-La Roche164 enrolled

Overview

This randomized, single center, adaptive single ascending dose (Part 1) and multiple ascending dose (Part 2) study is designed to assess the safety, tolerability, pharmacokinetic, and pharmacodynamics following an oral administration of RO6889450 versus placebo in healthy volunteers. The anticipated duration of this study is approximately 18 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

164

Conditions

Healthy Volunteer

Interventions

PlaceboDRUG

RO6889450DRUG

Eligibility

Sex: ALLMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * A body mass index (BMI) between 18 to 30 kilogram per square meter (kg/m\^2) inclusive * Body weight in the range of 50 to 100 kilogram (kg) and right-handed - Part 2 only * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm * Fluent in the language of the Investigator and study staff (including raters) * Able to participate and comply with the study restrictions Exclusion Criteria: Part 1 and Part 2: * Disorders of the central nervous system (CNS), psychiatric disorders, behavioral disturbances * Participants who, in the Investigator's judgment, pose a suicidal or homicidal risk * Any personal or familial history (first degree) of seizures, epilepsy or other convulsive condition * Positive family history of psychosis or mood disorders up to first degree relative * Angle closure glaucoma, history or current significant ophthalmologic or neurologic condition that would adversely affect the pupillometry assessment * Suspicion of regular consumption of drug of abuse and/or any history of alcohol addiction with positive urine drug screen and/or positive alcohol urine test, or regular smoker * Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus antibody (HIV 1 and 2) * Any prescribed or OTC medications (including vitamins or herbal remedies) taken within 4 weeks prior to first dosing or within 5 times the elimination half-life of the medication prior to first dosing (whichever is longer) * Taking any nutrients known to modulate CYP3A activity (e.g., grapefruit juice; Seville orange) within 2 weeks prior to administration of study drugs * Clinically significant abnormalities in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis) * Participation in an investigational drug or device study within 90 days prior to screening * Dietary restrictions that would prohibit the consumption of standardized meals * Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the participant in this study Part 2: * Contraindications for magnetic resonance imaging (MRI) scans or any brain/head abnormalities restricting MRI eligibility. Any sensorial impairment such as deafness and reduced visual acuity which cannot be corrected in the fMRI scanner * Use of any psychoactive medication, or medications known to have effects on CNS or blood flow taken within 4 weeks prior to first dosing or within 5 times the elimination half-life of the medication prior to first dosing (whichever is longer) * Fulfilment of any of the MRI contraindications on the standard radiography screening questionnaire

Locations (1)

PRA Health Sciences Early Development Services

Zuidlaren, Netherlands

Outcomes

Primary Outcomes

Percentage of Participants With Dose Limiting Toxicities After Single Ascending Dose (SAD) - Part 1

Time frame: up to 22 days

Area Under the Curve from Time Zero to end of dosing interval (AUCtau) After Multiple Oral Ascending Doses - Part 2

Time frame: Part 2: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 1; predose on Days 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 14, Days 15, 16, 17, 19, 20, 21

Percentage of Participants With Dose Limiting Toxicities After Multiple Oral Ascending Doses (MAD) - Part 2

Time frame: up to 35 days

Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 to inf)] After Single Ascending Dose - Part 1

Time frame: Part 1: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours (hr) postdose on Day 1; Day 2, 3, 4, 6, 7, 8

RO6889450 Maximum Plasma Concentration (Cmax) After Single Oral Ascending Doses

Time frame: Part 1: predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours postdose on Day 1, Days 2, 3, 4, 6, 7, 8

RO6889450 Maximum Plasma Concentration (Cmax) After Multiple Oral Ascending Doses

Time frame: Part 2: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours postdose on Day 1, predose on Days 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours postdose on Day 14, Days 15, 16, 17, 19, 20, 21

RO6889450 Minimum Observed Plasma Trough Concentration (Cmin)

Time frame: Part 2: predose on Days 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours postdose on Day 14, Days 15

Secondary Outcomes

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Time to Reach Maximum Observed Plasma Concentration (Tmax) After Multiple Ascending Dose - Part 2

Time frame: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose, Days 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 14, Days 15, 16, 17, 19, 20, 21

Terminal Rate Constant After Multiple Ascending Dose - Part 2

Time frame: Part 2: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 1, predose on Days 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, predose, 0.5,1,1.5, 2, 2.5, 3,4, 6, 8, 12, 16 hr postdose on Day 14, Days 15, 16, 17, 19, 20, 21

Apparent Terminal Half-Life (t1/2) After Multiple Ascending Dose - Part 2

Time frame: Part 2: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 1, predose on Days 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, predose, 0.5, 1, 1.5, 2, 2.5, 3,4, 6, 8, 12, 16 hr postdose on Day 14, Days 15, 16, 17, 19, 20, 21

Apparent Oral Clearance (CL/F) After Multiple Ascending Dose - Part 2

Time frame: Part 2: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 1, predose on Days 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 14, Days 15, 16, 17, 19, 20, 21

Cumulative Amount Excreted Unchanged in Urine (Ae) After Multiple Ascending Dose - Part 2

Time frame: Part 2: predose, 0 to 6, 6 to 12, 12 to 24 hours postdose on Day 1, 14, 24 to 48 and 48 to 72 hours after Day 14 dosing

Renal Clearance (CLR) After Multiple Ascending Dose - Part 2

Time frame: Part 2: predose, 0 to 6, 6 to 12, 12 to 24 hours postdose on Day 1, 14, 24 to 48 and 48 to 72 hours after Day 14 dosing

Fasting Glucose Concentrations After Multiple Ascending Dose - Part 2

Time frame: Part 2: Baseline, Days 7, 15, 17

Plasma Concentration of Prolactin - Part 2

Time frame: Part 2: Day 1, 14, 15

Scotopic Pupil Diameter as Assessed by Pupillometer - Part 2

Time frame: Part 2: Day 1, 2, 14, 15

Time to Reach Maximum Observed Plasma Concentration (Tmax) After Single Ascending Dose - Part 1

Time frame: Part 1: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours (hr) postdose on Day 1, Days 2, 3, 4, 6, 7, 8

Last Measurable Concentration (Clast) After Single Ascending Dose - Part 1

Time frame: Part 1: predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours postdose on Day 1, Days 2, 3, 4, 6, 7, 8

Time to Last Measurable Concentration (Tlast) After Single Ascending Dose - Part 1

Time frame: Part 1: predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours postdose on Day 1, Days 2, 3, 4, 6, 7, 8

Terminal Rate Constant After Single Ascending Dose - Part 1

Time frame: Part 1: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 1, Days 2, 3, 4, 6, 7, 8

Apparent Terminal Half-Life (t1/2) After Single Ascending Dose - Part 1

Time frame: Part 1: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 1, Days 2, 3, 4, 6, 7, 8

Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours Post-Dose (AUC0-24h) After Single Ascending Dose - Part 1

Time frame: Part 1: predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours postdose on Day 1, Days 2, 3, 4, 6, 7, 8

Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUC0-last) After Single Ascending Dose - Part 1

Time frame: Part 1: predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours postdose on Day 1, Days 2, 3, 4, 6, 7, 8

Apparent Oral Clearance (CL/F) After Single Ascending Dose - Part 1

Time frame: Part 1: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hr postdose on Day 1, Days 2, 3, 4, 6, 7, 8

Cumulative Amount Excreted Unchanged in the Urine (Ae) After Single Ascending Dose - Part 1

Time frame: Part 1: predose, 0 to 6, 6 to 12, 12 to 24 hours postdose on Day 1, 24 to 48, 48 to 72 hours after Day 1 dosing

Renal Clearance (CLR) After Single Ascending Dose - Part 1

Time frame: Part 1: predose, 0 to 6, 6 to 12, 12 to 24 hours postdose on Day 1, 24 to 48, 48 to 72 hours after Day 1 dosing

Accumulation Ratio for AUCtau (RAUC), Calculated as Day 14 AUC0-tau/Day 1 AUC0-tau - Part 2

Time frame: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 hours (hr) postdose on Day 1; predose, 0.5,1,1.5, 2, 2.5, 3,4, 6, 8, 12, 16, 24 hr postdose on Day 14

Accumulation Ratio for Cmax (RCmax), Calculated as Day 14 Cmax / Day 1 Cmax - Part 2

Time frame: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours (hr) postdose on Day 1; predose, 0.5,1,1.5, 2, 2.5, 3,4, 6, 8, 12, 16, 24 hr postdose on Day 14

Accumulation Ratio for Ctrough RCtrough, Calculated as Day 14 Ctrough / Day 1 Ctrough - Part 2

Time frame: predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours (hr) postdose on Day 1; predose, 0.5,1,1.5, 2, 2.5, 3,4, 6, 8, 12, 16, 24 hr postdose on Day 14

Fasting Glucose Concentrations After Single - Part 1

Time frame: Part 1: Baseline, Day 4

Change From Baseline in Glucose Level at Day 14 - Part 2

Time frame: Baseline, Day 14

Change From Baseline in Insulin Level at Day 14 - Part 2

Time frame: Baseline, Day 14

Change From Baseline in C-peptide Level at Day 14 - Part 2

Time frame: Baseline, Day 14

Change From Baseline in Gastric Inhibitory Polypeptide (GIP) Level at Day 14 - Part 2

Time frame: Baseline, Day 14

Change From Baseline in Glucagon-like Peptide-1 (GLP-1) Level at Day 14 - Part 2

Time frame: Baseline, Day 14

Columbia Suicide-Severity Rating Scale (C-SSRS) Scores - Part 1

Time frame: Part 1: Day 4

Columbia Suicide-Severity Rating Scale (C-SSRS) Scores - Part 2

Time frame: Part 2: Day 15

Capillary Blood Glucose Levels - Part 1

Time frame: Part 1: Baseline through Day 4

Capillary Blood Glucose Levels - Part 2

Time frame: Part 2: Baseline through Day 17

Urine Concentration of Dopamine Metabolite - Part 2

Time frame: Baseline, Day 12, Day 13

Plasma Concentration of Prolactin - Part 1

Time frame: Part 1: Day 1, Day 2

Change From Baseline in Body Weight at Days 7 and 15 - Part 2

Time frame: Baseline, Day 7, 15

Addiction Research Center Inventory (ARCI-49) Questionnaire Score - Part 2

Time frame: Baseline, Day 1, 7, 14

Scotopic Pupil Diameter as Assessed by Pupillometer - Part 1

Time frame: Part 1: Day 1, 2

Change From Baseline in Regional Cerebral Blood Flow (CBF), as Assessed by Functional Magnetic Resonance Imaging (fMRI) at Days 7 or 8, 12 or 13

Time frame: Baseline, Day 7 or 8, 12 or 13

Facial Expression Recognition Task (FERT) Score, as Assessed by Emotional Test Battery (ETB) - Part 2

Time frame: Baseline, Day 12 or 13

Reward Learning Task Score, as Assessed by Effort-Based Paradigms - Part 2

Time frame: Baseline, Day 12 or 13