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

Phase 1
Completed
Conditions
Healthy Volunteer
Interventions
Drug: Placebo
Drug: RO6889450
Registration Number
NCT02699372
Lead Sponsor
Hoffmann-La Roche
Brief Summary

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.

Detailed Description

Not available

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
164
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
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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
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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
PlaceboPlaceboHealthy volunteers will receive the placebo equivalent to RO6889450 as oral capsules.
RO6889450: Part 1 Single Ascending Dose (SAD)RO6889450Participants will undergo a series of screening visits prior to treatment and 4 weeks follow-up. Healthy volunteers will be enrolled in up to 7 dose groups (5 milligram \[mg\] to 450 mg) and will receive single oral dose of RO6889450 in the morning of the Day 1.
RO6889450: Part 2 Multiple Ascending Dose (MAD)RO6889450The starting dose for Part 2 MAD will be determined by analysis of safety and pharmacokinetic data of Part 1 SAD. All participants will receive RO6889450 orally for 14 days.
Primary Outcome Measures
NameTimeMethod
RO6889450 Minimum Observed Plasma Trough Concentration (Cmin)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
Percentage of Participants With Dose Limiting Toxicities After Single Ascending Dose (SAD) - Part 1up to 22 days
Area Under the Curve from Time Zero to end of dosing interval (AUCtau) After Multiple Oral Ascending Doses - Part 2Part 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 2up to 35 days
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 to inf)] After Single Ascending Dose - Part 1Part 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 DosesPart 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 DosesPart 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
Secondary Outcome Measures
NameTimeMethod
Time to Reach Maximum Observed Plasma Concentration (Tmax) After Multiple Ascending Dose - Part 2predose, 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
Cumulative Amount Excreted Unchanged in Urine (Ae) After Multiple Ascending Dose - Part 2Part 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 2Part 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 2Part 2: Baseline, Days 7, 15, 17
Terminal Rate Constant After Multiple Ascending Dose - Part 2Part 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 2Part 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 2Part 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
Fasting Glucose Concentrations After Single - Part 1Part 1: Baseline, Day 4
Change From Baseline in Glucose Level at Day 14 - Part 2Baseline, Day 14
Change From Baseline in Insulin Level at Day 14 - Part 2Baseline, Day 14
Change From Baseline in C-peptide Level at Day 14 - Part 2Baseline, Day 14
Change From Baseline in Gastric Inhibitory Polypeptide (GIP) Level at Day 14 - Part 2Baseline, Day 14
Change From Baseline in Glucagon-like Peptide-1 (GLP-1) Level at Day 14 - Part 2Baseline, Day 14
Columbia Suicide-Severity Rating Scale (C-SSRS) Scores - Part 1Part 1: Day 4
Columbia Suicide-Severity Rating Scale (C-SSRS) Scores - Part 2Part 2: Day 15
Capillary Blood Glucose Levels - Part 1Part 1: Baseline through Day 4
Capillary Blood Glucose Levels - Part 2Part 2: Baseline through Day 17
Plasma Concentration of Prolactin - Part 2Part 2: Day 1, 14, 15
Scotopic Pupil Diameter as Assessed by Pupillometer - Part 2Part 2: Day 1, 2, 14, 15
Time to Reach Maximum Observed Plasma Concentration (Tmax) After Single Ascending Dose - Part 1Part 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 1Part 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 1Part 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 1Part 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 1Part 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 1Part 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 1Part 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 1Part 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 1Part 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 1Part 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 2predose, 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 2predose, 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 2predose, 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
Urine Concentration of Dopamine Metabolite - Part 2Baseline, Day 12, Day 13
Plasma Concentration of Prolactin - Part 1Part 1: Day 1, Day 2
Change From Baseline in Body Weight at Days 7 and 15 - Part 2Baseline, Day 7, 15
Addiction Research Center Inventory (ARCI-49) Questionnaire Score - Part 2Baseline, Day 1, 7, 14
Scotopic Pupil Diameter as Assessed by Pupillometer - Part 1Part 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 13Baseline, Day 7 or 8, 12 or 13
Facial Expression Recognition Task (FERT) Score, as Assessed by Emotional Test Battery (ETB) - Part 2Baseline, Day 12 or 13
Reward Learning Task Score, as Assessed by Effort-Based Paradigms - Part 2Baseline, Day 12 or 13

Trial Locations

Locations (1)

PRA Health Sciences Early Development Services

🇳🇱

Zuidlaren, Netherlands

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