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

NCT ID: NCT02321384

Last Updated: 2017-04-05

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-15
• Study Completion Date: 2015-11-26

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

A: SAD Cohorts - RO6889678/Matching Placebo

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

RO6889678

Intervention Type: 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.

B: MAD Cohorts - RO6889678/Matching Placebo

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

RO6889678

Intervention Type: 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.

Midazolam

Intervention Type: 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.

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

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

RO6889678

Intervention Type: 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.

Midazolam

Intervention Type: 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.

Ritonavir

Intervention Type: 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.

Interventions

Placebo

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.

Intervention Type: DRUG

RO6889678

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.

Intervention Type: DRUG

Midazolam

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.

Intervention Type: DRUG

Ritonavir

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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Centre For Human Drug Research; Research

Leiden, , Netherlands

Countries

Netherlands

Other Identifiers

2014-002297-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NP29454

Identifier Type: -

Identifier Source: org_study_id