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

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ClinicalTrials.gov Identifier: NCT02699372
Recruitment Status : Completed
First Posted : March 4, 2016
Last Update Posted : November 24, 2017
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Healthy Volunteer Drug: Placebo Drug: RO6889450 Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 164 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Single-center, Randomized, Investigator/Subject-Blind, Adaptive Single-ascending Dose (Part 1) and Multiple Ascending Dose (Part 2), Placebo-Controlled, Parallel Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of RO6889450 Following Oral Administration in Healthy Subjects
Actual Study Start Date : March 21, 2016
Actual Primary Completion Date : April 14, 2017
Actual Study Completion Date : April 14, 2017

Arm Intervention/treatment
Placebo Comparator: Placebo
Healthy volunteers will receive the placebo equivalent to RO6889450 as oral capsules.
Drug: Placebo
Experimental: RO6889450: Part 1 Single Ascending Dose (SAD)
Participants 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.
Drug: RO6889450
Experimental: RO6889450: Part 2 Multiple Ascending Dose (MAD)
The 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.
Drug: RO6889450



Primary Outcome Measures :
  1. Percentage of Participants With Dose Limiting Toxicities After Single Ascending Dose (SAD) - Part 1 [ Time Frame: up to 22 days ]
  2. 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 ]
  3. Percentage of Participants With Dose Limiting Toxicities After Multiple Oral Ascending Doses (MAD) - Part 2 [ Time Frame: up to 35 days ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. Fasting Glucose Concentrations After Multiple Ascending Dose - Part 2 [ Time Frame: Part 2: Baseline, Days 7, 15, 17 ]
  8. Plasma Concentration of Prolactin - Part 2 [ Time Frame: Part 2: Day 1, 14, 15 ]
  9. Scotopic Pupil Diameter as Assessed by Pupillometer - Part 2 [ Time Frame: Part 2: Day 1, 2, 14, 15 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 ]
  15. 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 ]
  16. 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 ]
  17. 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 ]
  18. 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 ]
  19. 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 ]
  20. 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 ]
  21. 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 ]
  22. 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 ]
  23. Fasting Glucose Concentrations After Single - Part 1 [ Time Frame: Part 1: Baseline, Day 4 ]
  24. Change From Baseline in Glucose Level at Day 14 - Part 2 [ Time Frame: Baseline, Day 14 ]
  25. Change From Baseline in Insulin Level at Day 14 - Part 2 [ Time Frame: Baseline, Day 14 ]
  26. Change From Baseline in C-peptide Level at Day 14 - Part 2 [ Time Frame: Baseline, Day 14 ]
  27. Change From Baseline in Gastric Inhibitory Polypeptide (GIP) Level at Day 14 - Part 2 [ Time Frame: Baseline, Day 14 ]
  28. Change From Baseline in Glucagon-like Peptide-1 (GLP-1) Level at Day 14 - Part 2 [ Time Frame: Baseline, Day 14 ]
  29. Columbia Suicide-Severity Rating Scale (C-SSRS) Scores - Part 1 [ Time Frame: Part 1: Day 4 ]
  30. Columbia Suicide-Severity Rating Scale (C-SSRS) Scores - Part 2 [ Time Frame: Part 2: Day 15 ]
  31. Capillary Blood Glucose Levels - Part 1 [ Time Frame: Part 1: Baseline through Day 4 ]
  32. Capillary Blood Glucose Levels - Part 2 [ Time Frame: Part 2: Baseline through Day 17 ]
  33. Urine Concentration of Dopamine Metabolite - Part 2 [ Time Frame: Baseline, Day 12, Day 13 ]
  34. Plasma Concentration of Prolactin - Part 1 [ Time Frame: Part 1: Day 1, Day 2 ]
  35. Change From Baseline in Body Weight at Days 7 and 15 - Part 2 [ Time Frame: Baseline, Day 7, 15 ]
  36. Addiction Research Center Inventory (ARCI-49) Questionnaire Score - Part 2 [ Time Frame: Baseline, Day 1, 7, 14 ]
  37. Scotopic Pupil Diameter as Assessed by Pupillometer - Part 1 [ Time Frame: Part 1: Day 1, 2 ]
  38. 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 ]
  39. Facial Expression Recognition Task (FERT) Score, as Assessed by Emotional Test Battery (ETB) - Part 2 [ Time Frame: Baseline, Day 12 or 13 ]
  40. Reward Learning Task Score, as Assessed by Effort-Based Paradigms - Part 2 [ Time Frame: Baseline, Day 12 or 13 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02699372


Locations
Netherlands
PRA Health Sciences Early Development Services
Zuidlaren, Netherlands, 9471 GP
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02699372     History of Changes
Other Study ID Numbers: BP30134
2015-005509-35 ( EudraCT Number )
First Posted: March 4, 2016    Key Record Dates
Last Update Posted: November 24, 2017
Last Verified: November 2017

Keywords provided by Hoffmann-La Roche:
Healthy Volunteers