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

NCT02321384 | Terminated Phase 1

• 2 other identifiers: NP294542014-002297-36
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteer

Outcome Measures

Primary Outcomes (29)

• Percentage of Participants With Adverse Events

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

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

  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

  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

  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

  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

  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

  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

  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

  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

  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

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

  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: Plasma Trough Concentration (Ctrough) of RO6889678

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

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

  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: Accumulation Index of RO6889678

  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: Ae of RO6889678

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

• MAD Cohort: CLR of RO6889678

  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

  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

  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

  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

  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

  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

  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

  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

• RTV-Boosted MAD Cohort: Tmax of RTV

  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

• RTV-Boosted MAD Cohort: AUC0-tau of RTV

  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

• RTV-Boosted MAD Cohort: Ctrough of RTV

  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

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

  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

• RTV-Boosted MAD Cohort: Accumulation Index of RTV

  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

Secondary Outcomes (15)

• MAD Cohort: Cmax of Midazolam

  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

  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

  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

  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

  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

Study Arms (3)

A: SAD Cohorts - RO6889678/Matching Placebo

EXPERIMENTAL

Healthy participants will be enrolled into 1 of 6 planned SAD cohorts to receive single dose of RO6889678/matching placebo in fasted state as per anticipated dose escalation sequence (30 milligrams \[mg\], 100 mg, 300 mg, 600 mg, 1000 mg and 1500 mg). Cohort 1 will be split in 2 groups: 2 participants will be dosed 1 day (1 on RO6889678 and 1 on matching placebo) and 3 participants (2 on RO6889678 and 1 on matching placebo) will be dosed at least 24 hours afterward following satisfactory safety assessment for first 2 participants. Cohort 2 \& beyond will include 8 healthy participants with 6 participants randomly assigned to RO6889678 \& 2 randomly assigned to placebo. Participants who will tolerate fasted dose and agree to continue in food-effect SAD cohort, will receive single dose (dose level, either 300 mg or 600 mg, decided based on PK and safety data of first 2 SAD cohorts) of RO6889678/matching placebo with US FDA recommended high-fat and high-calorie breakfast on Day 16.

Drug: Placebo; Drug: RO6889678

B: MAD Cohorts - RO6889678/Matching Placebo

EXPERIMENTAL

Healthy participants will be enrolled into 1 of 4 planned MAD cohorts to receive RO6889678 or matching placebo (at a dose that will be decided as per the safety, tolerability and PK data from SAD 4 cohort) twice daily (BID) for 14 days except for Day 14, where only one dose in the morning will be given. Each of the MAD cohorts will include 8 healthy participants with 6 participants randomly assigned to RO6889678 and 2 participants randomly assigned to placebo. All participants enrolled to the MAD cohorts will receive an oral microdose of midazolam (100 micrograms \[mcg\]) before (Day -1) and after (Day 14) the repeat treatment with RO6889678 or matching placebo.

Drug: Placebo; Drug: RO6889678; Drug: Midazolam

C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV

EXPERIMENTAL

Healthy participants will be enrolled in up to 3 SAD cohorts (2 compulsory and 1 optional) and up to 3 MAD cohorts (1 compulsory and 2 optional) to receive RO6889678 in combination with RTV in fed state. Participants of the first 2 RTV-boosted SAD cohorts will receive 100 mg RO6889678 + 100 mg RTV and 300 mg RO6889678 + 100 mg RTV respectively. Based on the PK and safety evaluation of the first 2 RTV-boosted SAD cohorts, another SAD cohort may be enrolled to receive a different dose of RO6889678 in combination with RTV. MAD RTV-boosted cohort will start based on the safety, tolerability and PK data of the RTV-boosted SAD cohorts. All participants enrolled to the RTV-boosted MAD cohorts will receive RO6889678 or placebo together with RTV on BID schedule for 14 days, and additionally an oral microdose of midazolam (100 mcg) before (Day -1) and after (Day 14) the treatment.

Drug: Placebo; Drug: RO6889678; Drug: Midazolam; Drug: Ritonavir

Interventions

Placebo DRUG

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.

A: SAD Cohorts - RO6889678/Matching Placebo; B: MAD Cohorts - RO6889678/Matching Placebo; C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV

RO6889678 DRUG

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.

A: SAD Cohorts - RO6889678/Matching Placebo; B: MAD Cohorts - RO6889678/Matching Placebo; C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV

Midazolam DRUG

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.

B: MAD Cohorts - RO6889678/Matching Placebo; C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV

Ritonavir DRUG

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.

C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (1)

Centre For Human Drug Research; Research

Leiden, 2333, Netherlands

Location

MeSH Terms

Interventions

Midazolam; Ritonavir

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2014
• First Posted: December 22, 2014
• Study Start: December 15, 2014
• Primary Completion: November 26, 2015
• Study Completion: November 26, 2015
• Last Updated: April 5, 2017

Record last verified: 2017-04

Locations

NL (1)