Healthy VolunteerPhase 1NCT02321384
A Study to Investigate the Safety, Tolerability and Pharmacokinetics of RO6889678 and the Combination of RO6889678 With Ritonavir in Healthy Participants
A Phase 1 study testing RO6889678, Midazolam and Ritonavir in people with Healthy Volunteer, run by Hoffmann-La Roche at 1 site in Netherlands.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteer
- What is being tested?
- RO6889678, Midazolam and Ritonavir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 100 participants
- Where
- 1 siteNetherlands
- Study dates
- 15 Dec 2014to 26 Nov 2015
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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
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
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
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.
RO6889678Drug
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.
MidazolamDrug
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.
RitonavirDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Placebo; Drug: RO6889678; Drug: Midazolam; Drug: Ritonavir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants With Adverse Events
Measured: From screening to the end of follow-up (up to 12 weeks)
SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO6889678
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Pre-dose (0 hr before morning dose) on Days 2, 3, 4, 5, 7
MAD Cohort: Apparent Terminal Half-life (t1/2) of RO6889678
Measured: 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
Measured: 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
Measured: Pre-dose (0 hr), 0-4, 4-8, 8-12 hours post morning dose on Day 1 and 14
MAD Cohort: CLR of RO6889678
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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-inf of RO6889678
Measured: 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: Apparent Terminal t1/2 of RO6889678
Measured: 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: CL/F of RO6889678
Measured: 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: Ae of RO6889678
Measured: Pre-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 RO6889678
Measured: Pre-dose (0 hr) on Day 16; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 16 dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Dec 2014 (estimated)
- Study start15 Dec 2014
- Primary completion26 Nov 2015
- Study completion26 Nov 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Healthy VolunteerStudies of the same condition, open and under way.
- More trials run by Hoffmann-La RocheThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 100 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hoffmann-La Roche
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Trials, Study director, Hoffmann-La Roche
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02321384
- Sponsor's protocol ID
- NP29454
- Other IDs
- 2014-002297-36, 2014
- Status last verified
- Apr 2017
- First submitted
- 17 Dec 2014
- Last updated
- 5 Apr 2017
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT02321384
- Acronym / sponsor ID
- NP29454
- Conditions
- Healthy Volunteer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 100 participants (actual)
- Lead sponsor
- Hoffmann-La RocheIndustry (pharma, biotech, devices)
- Study start
- 15 Dec 2014 (actual)
- Primary completion
- 26 Nov 2015 (actual)
- Study completion
- 26 Nov 2015 (actual)
- First posted
- 22 Dec 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| A: SAD Cohorts - RO6889678/Matching Placebo | Experimental | Drug: Placebo, Drug: RO6889678Healthy 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. |
| B: MAD Cohorts - RO6889678/Matching Placebo | Experimental | Drug: Placebo, Drug: RO6889678, Drug: MidazolamHealthy 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. |
| C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV | Experimental | Drug: Placebo, Drug: RO6889678, Drug: Midazolam, Drug: RitonavirHealthy 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. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboPlacebo 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. | Drug | A: SAD Cohorts - RO6889678/Matching Placebo, B: MAD Cohorts - RO6889678/Matching Placebo, C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV |
| RO6889678RO6889678 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. | Drug | A: SAD Cohorts - RO6889678/Matching Placebo, B: MAD Cohorts - RO6889678/Matching Placebo, C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV |
| MidazolamSingle dose of 100 mcg midazolam solution will be administered orally, before (Day -1) and after (Day 14) the treatment with RO6889678 or matching placebo. | Drug | B: MAD Cohorts - RO6889678/Matching Placebo, C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV |
| RitonavirRTV 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. | Drug | C:RTV-Boosted SAD & MAD Cohorts-RO6889678/Matching Placebo+RTV |
Primary outcome
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
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: Area Under the Plasma Concentration Versus Time Curve for a Dosing Interval (AUC0-tau) 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: 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
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: Accumulation Index 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: 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
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
RTV-Boosted MAD Cohort: Tmax of RTV
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
RTV-Boosted MAD Cohort: AUC0-tau of RTV
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
RTV-Boosted MAD Cohort: Ctrough of RTV
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
RTV-Boosted MAD Cohort: Apparent Terminal t1/2 of RTV
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
RTV-Boosted MAD Cohort: Accumulation Index of RTV
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
15 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
Food-effect SAD Cohort: AUC0-inf 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: Apparent Terminal t1/2 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: CL/F 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: Ae of RO6889678
Time frame: Pre-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 RO6889678
Time frame: Pre-dose (0 hr) on Day 16; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 16 dose
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2017.
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Screening Protocol
Pain
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Trials study director
Hoffmann-La Roche
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing RO6889678, Midazolam and Ritonavir in people with Healthy Volunteer, run by Hoffmann-La Roche at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 5 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With Adverse Events (time frame: From screening to the end of follow-up (up to 12 weeks)). The study lists 29 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2017.