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

A Single-Center, Randomized, Double-Blind, Single and Multiple Ascending Dose, Placebo-Controlled Study to Investigate the Safety, Tolerability and Pharmacokinetics of RO6889678 and the Combination of RO6889678 With Ritonavir Following Oral Administration, the Effect of Food on the Pharmacokinetics of RO6889678 and the Effect of Multiple Oral Dosing of RO6889678 and the Combination of RO6889678 With Ritonavir on the Pharmacokinetics of Midazolam in Healthy Subjects

Status
Terminated
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02321384
Enrollment
100
Registered
2014-12-22
Start date
2014-12-15
Completion date
2015-11-26
Last updated
2017-04-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteer

Brief summary

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.

Interventions

DRUGPlacebo

Placebo matched to RO6889678 will be administered orally as a single dose on Day 1 in SAD cohorts and multiple doses BID from Day 1 to Day 14 (no second BID dose on Day 14) in MAD cohorts.

DRUGRO6889678

RO6889678 will be administered orally as a single dose on Day 1 in SAD cohorts and multiple doses BID from Day 1 to Day 14 (no second BID dose on Day 14) in MAD cohorts.

DRUGMidazolam

Single dose of 100 mcg midazolam solution will be administered orally, before (Day -1) and after (Day 14) the treatment with RO6889678 or matching placebo.

DRUGRitonavir

RTV will be administered orally as a single dose on Day 1 in RTV-boosted SAD cohorts and multiple doses BID from Day 1 to Day 14 (no second BID dose on Day 14) in RTV-boosted MAD cohorts.

Sponsors

Hoffmann-La Roche
Lead SponsorINDUSTRY

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes

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

Design outcomes

Primary

MeasureTime frame
RTV-Boosted MAD Cohort: Accumulation Index of RTVPre-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: Apparent Terminal Half-life (t1/2) of RO6889678Pre-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: Accumulation Index of RO6889678Pre-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: Ae of RO6889678Pre-dose (0 hr), 0-4, 4-8, 8-12 hours post morning dose on Day 1 and 14
MAD Cohort: CLR of RO6889678Pre-dose (0 hr), 0-4, 4-8, 8-12 hours post morning dose on Day 1 and 14
RTV-Boosted SAD Cohort: Cmax of RTVPre-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 RTVPre-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 RTVPre-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 RTVPre-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 RTVPre-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 RTVPre-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 RTVPre-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
RTV-Boosted MAD Cohort: AUC0-tau of RTVPre-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
RTV-Boosted MAD Cohort: Tmax of RTVPre-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
RTV-Boosted MAD Cohort: Ctrough of RTVPre-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
RTV-Boosted MAD Cohort: Apparent Terminal t1/2 of RTVPre-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
SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO6889678Pre-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
Percentage of Participants With Adverse EventsFrom screening to the end of follow-up (up to 12 weeks)
SAD Cohort: Time to Reach Cmax (Tmax) of RO6889678Pre-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 RO6889678Pre-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 RO6889678Pre-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 RO6889678Pre-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 RO6889678Pre-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 RO6889678Pre-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 RO6889678Pre-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 RO6889678Pre-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 RO6889678Pre-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: Area Under the Plasma Concentration Versus Time Curve for a Dosing Interval (AUC0-tau) of RO6889678Pre-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: Plasma Trough Concentration (Ctrough) of RO6889678Pre-dose (0 hr before morning dose) on Days 2, 3, 4, 5, 7

Secondary

MeasureTime frame
Tmax of MidazolamPre-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 MidazolamPre-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 MidazolamPre-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 MidazolamPre-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 MidazolamPre-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 MidazolamPre-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 RO6889678Pre-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 RO6889678Pre-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 RO6889678Pre-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-inf of RO6889678Pre-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: Apparent Terminal t1/2 of RO6889678Pre-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: CL/F of RO6889678Pre-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: Ae of RO6889678Pre-dose (0 hr) on Day 16; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 16 dose
Food-effect SAD Cohort: CLR of RO6889678Pre-dose (0 hr) on Day 16; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 16 dose
MAD Cohort: Cmax of MidazolamPre-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

Countries

Netherlands

Outcome results

None listed

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026