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

Healthy Volunteer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02321384
• Other study ID #: NP29454
• Secondary ID: 2014-002297-36
• Status: Terminated
• Phase: Phase 1
• First received: December 17, 2014
• Last updated: April 3, 2017
• Start date: December 15, 2014
• Est. completion date: November 26, 2015

Study information

• Verified date: April 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 100
• Est. completion date: November 26, 2015
• Est. primary completion date: November 26, 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy Volunteer

Intervention

Drug:
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Netherlands	Centre For Human Drug Research; Research	Leiden

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Adverse Events		From screening to the end of follow-up (up to 12 weeks)
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	MAD Cohort: Plasma Trough Concentration (Ctrough) of RO6889678		Pre-dose (0 hr before morning dose) on Days 2, 3, 4, 5, 7
Primary	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
Primary	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
Primary	MAD Cohort: Ae of RO6889678		Pre-dose (0 hr), 0-4, 4-8, 8-12 hours post morning dose on Day 1 and 14
Primary	MAD Cohort: CLR of RO6889678		Pre-dose (0 hr), 0-4, 4-8, 8-12 hours post morning dose on Day 1 and 14
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	MAD Cohort: Apparent Terminal t1/2 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
Secondary	MAD Cohort: CL/F 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
Secondary	Food-effect SAD Cohort: Cmax of RO6889678		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
Secondary	Food-effect SAD Cohort: Tmax of RO6889678		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
Secondary	Food-effect SAD Cohort: AUC0-last of RO6889678		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
Secondary	Food-effect SAD Cohort: AUC0-inf of RO6889678		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
Secondary	Food-effect SAD Cohort: Apparent Terminal t1/2 of RO6889678		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
Secondary	Food-effect SAD Cohort: CL/F of RO6889678		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
Secondary	Food-effect SAD Cohort: Ae of RO6889678		Pre-dose (0 hr) on Day 16; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 16 dose
Secondary	Food-effect SAD Cohort: CLR of RO6889678		Pre-dose (0 hr) on Day 16; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 16 dose