A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of TMC647055 in Combination With Ritonavir (Part 1) and the Co-administration of TMC435, TMC647055 and Ritonavir (Part 2) in Healthy Japanese Participants
- Conditions
- Healthy
- Interventions
- Registration Number
- NCT02064842
- Lead Sponsor
- Janssen R&D Ireland
- Brief Summary
The purpose of the study is to investigate the safety, tolerability, and pharmacokinetics of TMC647055 in combination with ritonavir (Part 1); potential pharmacokinetic drug-drug interactions between TMC435 and the combination of TMC647055 with ritonavir; and to evaluate the short-term safety and tolerability when TMC435, TMC647055 and Ritonavir are co-administered (Part 2) in healthy Japanese participants.
- Detailed Description
This is a single-center study which consists of 2 parts, sequentially conducted in 2 separate panels of 24 healthy adult Japanese participants each. Part 1 is a double-blinded (neither physician nor participant knows the treatment that the participant receives), placebo-controlled (placebo is compared with the study medication to test whether the study medication has a real effect in clinical study), randomized (the study medication is assigned by chance) single ascending dose (SAD) part which will consist of a screening phase, a treatment phase, and a follow-up visit. Part 1 will have 3 cohorts (Cohort A, B, and C) with 8 participants each and they will be randomly assigned to receive either a single oral dose of TMC647055 (6 participants) or placebo (2 participants) in combination with RTV. The study duration for each participant will be approximately 5 weeks from screening to follow-up visit as maximum in Part 1. Part 2 is an open-label, randomized, 3-way crossover part which will consist of a screening phase, 3 treatment phases, and a follow-up phase. Each of the 24 participants will receive Treatment A, B, and C in 6 sequences (Treatment ABC, BCA, CAB, ACB, BAC, and CBA) with a washout period of at least 7 days between consecutive treatments. Safety evaluation will include assessment of adverse events, clinical laboratory tests, vital signs, electrocardiogram, and physical examination. The study duration for each participant will be approximately 10 weeks from screening to follow-up visit as maximum.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 24
- Man or woman of Japanese descent who has resided outside Japan for no more than 5 years and whose parents and grandparents are Japanese as determined by participant's verbal report
- Must have signed an informed consent form
- Women must be of non-child-bearing potential (postmenopausal for at least 2 years, surgically sterile, or otherwise incapable of becoming pregnant)
- Women, except for postmenopausal women, should have a negative serum b-human chorionic gonadotropin pregnancy test at screening
- Men heterosexually active with a woman of childbearing potential must agree to use two effective methods of birth control, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of study medication
- Must have a body mass index between 16.0 and 30.0 kg/m2, inclusive, and body weight not less than 45 kg at screening
- History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use within the past 1 year which in the Investigator's opinion would compromise participant's safety and/or compliance with the study procedures
- Participant's with Hepatitis A, B, or C infection, or human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2) infection at study screening
- Female participants who are breastfeeding at screening
- History of liver or renal impairment, significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, neoplastic, or metabolic disturbances
- History of clinically relevant skin disease or history of allergy to any medication
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Sequence 3 (Treatment C-A-B) TMC647055 Participants in Part 2 will receive Treatment CAB in the following sequence - Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment A: TMC435 150 mg once daily on Days 1 to 7; and Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 3 (Treatment C-A-B) TMC435 Participants in Part 2 will receive Treatment CAB in the following sequence - Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment A: TMC435 150 mg once daily on Days 1 to 7; and Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 4 (Treatment A-C-B) TMC435 Participants in Part 2 will receive Treatment ACB in the following sequence - Treatment A: TMC435 150 mg once daily on Days 1 to 7; Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 5 (Treatment B-A-C) TMC647055 Participants in Part 2 will receive Treatment BAC in the following sequence - Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment A: TMC435 150 mg once daily on Days 1 to 7; and Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 5 (Treatment B-A-C) TMC435 Participants in Part 2 will receive Treatment BAC in the following sequence - Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment A: TMC435 150 mg once daily on Days 1 to 7; and Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 6 (Treatment C-B-A) TMC435 Participants in Part 2 will receive Treatment CBA in the following sequence - Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment A: TMC435 150 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 6 (Treatment C-B-A) Ritonavir (RTV) Participants in Part 2 will receive Treatment CBA in the following sequence - Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment A: TMC435 150 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. TMC647055 150 mg or placebo + ritonavir (RTV) TMC647055 Participants in Part 1 will receive a single oral dose of 150 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. TMC647055 150 mg or placebo + ritonavir (RTV) Placebo Participants in Part 1 will receive a single oral dose of 150 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. TMC647055 450 mg or placebo + RTV Placebo Participants in Part 1 will receive a single oral dose of 450 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. TMC647055 450 mg or placebo + RTV Ritonavir (RTV) Participants in Part 1 will receive a single oral dose of 450 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. TMC647055 600 mg or placebo + RTV Placebo Participants in Part 1 will receive a single oral dose of 600 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. TMC647055 600 mg or placebo + RTV Ritonavir (RTV) Participants in Part 1 will receive a single oral dose of 600 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. Sequence 1 (Treatment A-B-C) TMC435 Participants in Part 2 will receive Treatment ABC in the following sequence - Treatment A: TMC435 150 mg once daily on Days 1 to 7; Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 2 (Treatment B-C-A) TMC647055 Participants in Part 2 will receive Treatment BCA in the following sequence - Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment A: TMC435 150 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. TMC647055 150 mg or placebo + ritonavir (RTV) Ritonavir (RTV) Participants in Part 1 will receive a single oral dose of 150 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. Sequence 5 (Treatment B-A-C) Ritonavir (RTV) Participants in Part 2 will receive Treatment BAC in the following sequence - Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment A: TMC435 150 mg once daily on Days 1 to 7; and Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 1 (Treatment A-B-C) Ritonavir (RTV) Participants in Part 2 will receive Treatment ABC in the following sequence - Treatment A: TMC435 150 mg once daily on Days 1 to 7; Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 2 (Treatment B-C-A) Ritonavir (RTV) Participants in Part 2 will receive Treatment BCA in the following sequence - Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment A: TMC435 150 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 3 (Treatment C-A-B) Ritonavir (RTV) Participants in Part 2 will receive Treatment CAB in the following sequence - Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment A: TMC435 150 mg once daily on Days 1 to 7; and Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 4 (Treatment A-C-B) Ritonavir (RTV) Participants in Part 2 will receive Treatment ACB in the following sequence - Treatment A: TMC435 150 mg once daily on Days 1 to 7; Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 2 (Treatment B-C-A) TMC435 Participants in Part 2 will receive Treatment BCA in the following sequence - Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment A: TMC435 150 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 6 (Treatment C-B-A) TMC647055 Participants in Part 2 will receive Treatment CBA in the following sequence - Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment A: TMC435 150 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. TMC647055 450 mg or placebo + RTV TMC647055 Participants in Part 1 will receive a single oral dose of 450 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. TMC647055 600 mg or placebo + RTV TMC647055 Participants in Part 1 will receive a single oral dose of 600 mg of TMC647055 or placebo with 30 mg of RTV on Day 1. Sequence 1 (Treatment A-B-C) TMC647055 Participants in Part 2 will receive Treatment ABC in the following sequence - Treatment A: TMC435 150 mg once daily on Days 1 to 7; Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant. Sequence 4 (Treatment A-C-B) TMC647055 Participants in Part 2 will receive Treatment ACB in the following sequence - Treatment A: TMC435 150 mg once daily on Days 1 to 7; Treatment C: TMC435 100 mg once daily + TMC647055 600 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7; and Treatment B: TMC435 75 mg once daily + TMC647055 450 mg once daily in combination with RTV 30 mg once daily on Days 1 to 7 with a washout period of 7 days between consecutive treatment sessions in each individual participant.
- Primary Outcome Measures
Name Time Method Part 1: Number of participants with adverse events following the administration of TMC647055 Up to Day 8 Assessment will be following single oral doses of TMC647055/Ritonavir 150/30 mg, 450/30 mg and 600/30 mg
Part 1: Maximum observed plasma concentration of TMC647055 Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 hours postdose); Day 2 (24 and 36 hours postdose); Day 3; and in case of early withdrawal (once between Day 6 to 8) Assessment will be following single oral doses of TMC647055/Ritonavir 150/30 mg, 450/30 mg and 600/30 mg
Part 1: The actual sampling time to reach the maximum observed plasma of TMC647055 Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 hours postdose); Day 2 (24 and 36 hours postdose); Day 3; and in case of early withdrawal (once between Day 6 to 8) Assessment will be following single oral doses of TMC647055/Ritonavir 150/30 mg, 450/30 mg and 600/30 mg
Part 1: The actual sampling time of last measurable plasma concentration of TMC647055 Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 hours postdose); Day 2 (24 and 36 hours postdose); Day 3; and in case of early withdrawal (once between Day 6 to 8) Assessment will be following single oral doses of TMC647055/Ritonavir 150/30 mg, 450/30 mg and 600/30 mg
Part 1: Area under curve (AUC) of TMC647055 Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 hours postdose); Day 2 (24 and 36 hours postdose); Day 3; and in case of early withdrawal (once between Day 6 to 8) AUC from time 0 up to 24 hours after dosing, from time 0 to the time of the last measurable concentration, and from time 0 to infinite time will be assessed. Assessment will be following single oral doses of TMC647055/Ritonavir 150/30 mg, 450/30 mg and 600/30 mg
Part 2: Maximum observed plasma concentration of TMC435 Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) Assessment will be following TMC435 75 mg co-administered with TMC647055/ritonavir 450/30 mg; TMC435 100 mg co-administered with TMC647055/ritonavir 600/30 mg; and TMC435 150 mg alone
Part 2: The actual sampling time to reach the maximum observed plasma of TMC435 Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) Assessment will be following TMC435 75 mg co-administered with TMC647055/ritonavir 450/30 mg; TMC435 100 mg co-administered with TMC647055/ritonavir 600/30 mg; and TMC435 150 mg alone
Part 2: Area under curve (AUC) of TMC435 Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) AUC from time 0 up to 24 hours after dosing will be assessed. Assessment will be following TMC435 75 mg co-administered with TMC647055/ritonavir 450/30 mg; TMC435 100 mg co-administered with TMC647055/ritonavir 600/30 mg; and TMC435 150 mg alone
Part 2: Maximum observed plasma concentration of TMC647055 Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) Assessment will be following TMC647055 600 mg co-administered with TMC435 100 mg and ritonavir 30 mg; and TMC647055 450 mg co-administered with TMC435 75 mg and ritonavir 30 mg
Part 2: The actual sampling time to reach the maximum observed plasma of TMC647055 Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) Assessment will be following TMC647055 600 mg co-administered with TMC435 100 mg and ritonavir 30 mg; and TMC647055 450 mg co-administered with TMC435 75 mg and ritonavir 30 mg
Part 2: Area under curve (AUC) of TMC647055 Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) AUC from time 0 up to 24 hours after dosing will be assessed. Assessment will be following TMC647055 600 mg co-administered with TMC435 100 mg and ritonavir 30 mg; and TMC647055 450 mg co-administered with TMC435 75 mg and ritonavir 30 mg
- Secondary Outcome Measures
Name Time Method Part 2: Maximum observed plasma concentration of ritonavir (RTV) Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) Assessment will be following RTV 30 mg co-administered with TMC435 75 mg and TMC647055 450 mg; and RTV 30 mg co-administered with TMC435 100 mg and TMC647055 600 mg
Part 2: The actual sampling time to reach the maximum observed plasma of ritonavir (RTV) Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) Assessment will be following RTV 30 mg co-administered with TMC435 75 mg and TMC647055 450 mg; and RTV 30 mg co-administered with TMC435 100 mg and TMC647055 600 mg
Part 2: Area under curve (AUC) of ritonavir (RTV) Day 1 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 2; Day 5; Day 6; Day 7 (predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose); Day 8; Day 9; Day 10; and end of treatment period or early withdrawal (once between Day 12 to 14) AUC from time 0 up to 24 hours after dosing will be assessed. Assessment will be following RTV 30 mg co-administered with TMC435 75 mg and TMC647055 450 mg; and RTV 30 mg co-administered with TMC435 100 mg and TMC647055 600 mg
Part 2: Number of participants with adverse events following the administration of TMC435 Up to Day 14 Assessment will be following TMC435 75 mg co-administered with TMC647055/ritonavir 450/30 mg; TMC435 100 mg co-administered with TMC647055/ritonavir 600/30 mg; and TMC435 150 mg alone