A Study to Investigate the Safety, Tolerability and Pharmacokinetics of RO6889678 and the Combination of RO6889678 With Ritonavir in Healthy Participants

Phase 1TerminatedNCT02321384

Hoffmann-La Roche100 enrolled

Overview

This study is a single-center, double-blind, randomized, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) study that will evaluate the safety, tolerability and pharmacokinetics (PK) of RO6889678 and the combination of RO6889678 with Ritonavir (RTV) following oral administration in healthy volunteers. The effect of food on the PK of RO6889678 and the effect of multiple dosing of RO6889678 and the combination of RO6889678 with RTV on the PK of a single oral microdose of midazolam will be evaluated. Healthy participants will be screened up to 28 days before randomization and sequentially enrolled into SAD and MAD unboosted and RTV-boosted cohorts, then randomly assigned to RO6889678 or matching placebo. In RTV-boosted cohorts participants will take RO6889678 in combination with RTV. To explore the effect of food on RO6889678 PK, a cohort of volunteers will participate in a two-period food effect sub-study. Participants enrolled in the MAD cohorts will be given an oral microdose of midazolam before and after the repeat treatment with RO6889678 to evaluate the drug-drug interaction potential of RO6889678.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

DOUBLE

Enrollment

100

Conditions

Healthy Volunteer

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead Electrocardiogram (ECG), hematology, blood chemistry, serology and urinalysis * A Body Mass Index (BMI) between 18 to 30 kilograms per square meter (kg/m\^2), inclusive * Female participants must be either surgically sterile (by means of hysterectomy and/or bilateral oophorectomy) or post-menopausal for at least one year (defined as amenorrhea greater than or equal to \[\>/=\] 12 consecutive months without another cause, and confirmed by follicle stimulating hormone level greater than \[\>\] 35 milli-international units per milliliter \[mIU/mL\]) * Male participants must agree to use two adequate methods of contraception with their female partners of childbearing potential, including a barrier method during the treatment period and for at least 2 months after the last dose of study drug Exclusion Criteria: * History or symptoms of any significant disease * Pregnant or lactating * Personal or family history of congenital long QT syndrome or sudden death * Significant acute infection, e.g. influenza, local infection, acute gastrointestinal symptoms or any other clinically significant illness within two weeks of dose administration * Clinically relevant ECG abnormalities on screening ECG * Participation in an investigational drug or device study within 90 days prior to screening * Medical or social conditions that would potentially interfere with the participant's ability to comply with the study visit schedule or the study assessments

Outcomes

Primary Outcomes

Percentage of Participants With Adverse Events

Time frame: From screening to the end of follow-up (up to 12 weeks)

SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO6889678

Time frame: Pre-dose (0 hour [hr]) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

SAD Cohort: Time to Reach Cmax (Tmax) of RO6889678

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

Outcome Measure: SAD Cohort: Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUC0-last) of RO6889678

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

SAD Cohort: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6889678

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

SAD Cohort: Apparent Terminal Half-life (t1/2) of RO6889678

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

SAD Cohort: Apparent Oral Clearance (CL/F) of RO6889678

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

RO6889678 Only SAD Cohort 3 and 6 and all RTV-Boosted SAD Cohorts: Cumulative Amount Excreted Unchanged in Urine (Ae) of RO6889678

Time frame: Pre-dose (0 hr) on Day 1; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 1 dose

RO6889678 Only SAD Cohort 3 and 6 and all RTV-Boosted SAD Cohorts: Renal Clearance (CLR) of RO6889678

Time frame: Pre-dose (0 hr) on Day 1; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 1 dose

MAD Cohort: Cmax of RO6889678

Time frame: Pre-dose (0 hr), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 & 12 hr after first dose on Day 1; pre-dose (0 hr before morning dose) on Days 2, 3, 4, 5, 7; and pre-dose (0 hr), 0.25,0.5,1,1.5,2,3,4,6,8,10,12,24,36,48,72 & 96 hr after last morning dose on Day 14

MAD Cohort: Tmax of RO6889678

MAD Cohort: Area Under the Plasma Concentration Versus Time Curve for a Dosing Interval (AUC0-tau) of RO6889678

MAD Cohort: Plasma Trough Concentration (Ctrough) of RO6889678

Time frame: Pre-dose (0 hr before morning dose) on Days 2, 3, 4, 5, 7

MAD Cohort: Apparent Terminal Half-life (t1/2) of RO6889678

MAD Cohort: Accumulation Index of RO6889678

MAD Cohort: Ae of RO6889678

Time frame: Pre-dose (0 hr), 0-4, 4-8, 8-12 hours post morning dose on Day 1 and 14

MAD Cohort: CLR of RO6889678

Time frame: Pre-dose (0 hr), 0-4, 4-8, 8-12 hours post morning dose on Day 1 and 14

RTV-Boosted SAD Cohort: Cmax of RTV

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

RTV-Boosted SAD Cohort: Tmax of RTV

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

RTV-Boosted SAD Cohort: AUC0-last of RTV

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

RTV-Boosted SAD Cohort: AUC0-inf of RTV

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

RTV-Boosted SAD Cohort: Apparent Terminal t1/2 of RTV

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

RTV-Boosted SAD Cohort: CL/F of RTV

Time frame: Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 1 dose

RTV-Boosted MAD Cohort: Cmax of RTV

RTV-Boosted MAD Cohort: Tmax of RTV

RTV-Boosted MAD Cohort: AUC0-tau of RTV

RTV-Boosted MAD Cohort: Ctrough of RTV

RTV-Boosted MAD Cohort: Apparent Terminal t1/2 of RTV

RTV-Boosted MAD Cohort: Accumulation Index of RTV

Secondary Outcomes

MAD Cohort: Cmax of Midazolam

Time frame: Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, 12, and 24 hr post-midazolam dose on Days -1 and 14

Tmax of Midazolam

Time frame: Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, 12, and 24 hr post-midazolam dose on Days -1 and 14

MAD Cohort: AUC0-last of Midazolam

Time frame: Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, 12, and 24 hr post-midazolam dose on Days -1 and 14

MAD Cohort: AUC0-inf of Midazolam

Time frame: Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, 12, and 24 hr post-midazolam dose on Days -1 and 14

MAD Cohort: Area Under the Plasma Concentration Versus Time Curve up to 6 h Post-dose (AUC0-6h) of Midazolam

Time frame: Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, 12, and 24 hr post-midazolam dose on Days -1 and 14

MAD Cohort: Apparent Terminal t1/2 of Midazolam

Time frame: Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, 12, and 24 hr post-midazolam dose on Days -1 and 14

MAD Cohort: CL/F of Midazolam

Time frame: Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, 12, and 24 hr post-midazolam dose on Days -1 and 14

Food-effect SAD Cohort: Cmax of RO6889678

Time frame: Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 16 dose

Food-effect SAD Cohort: Tmax of RO6889678

Time frame: Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 16 dose

Food-effect SAD Cohort: AUC0-last of RO6889678

Time frame: Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hr post Day 16 dose

A Study to Investigate the Safety, Tolerability and Pharmacokinetics of RO6889678 and the Combination of RO6889678 With Ritonavir in Healthy Participants

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes