PEPI-TiDP23-C103: First-in-Human Study to Examine the Safety, Tolerability, and Plasma Pharmacokinetics of Increasing Single and Repeated Oral Doses of TMC558445 and of a Combined Single Day Dosing of Oral TMC558445 and Oral TMC310911 and Also Oral Darunavir
Condition: HIV-1
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of the study is to determine the safety, tolerability and plasma pharmacokinetics
      (pk) (i.e., the levels of TMC558445 circulating in your blood over time) of increasing single
      oral doses of TMC558445 and of multiple increasing oral doses followed by a single dose of
      TMC310911 to assess the potential boosting effect on the latter compound. In this study, two
      investigational new drugs are involved, TMC558445 and TMC310911.

      The study has been amended as follows:

      TMC558445 will be administered either twice a day (b.i.d.) or once daily (q.d.). A single 300
      mg or 600 mg dose of TMC310911 will be administered under fasted or fed conditions. The
      boosting effect on Darunavir will be investigated.
    

Detailed description: 
      This is a First-in-Human Phase I, double-blind (neither physician or patient knows the name
      of the assigned study drug), randomized (study medication assigned by chance),
      placebo-controlled trial for TMC558445 to examine the safety, tolerability and plasma
      pharmacokinetics after increasing single oral doses of TMC558445 and after increasing oral
      repeated doses of TMC558445, followed by a single day dosing of TMC558445 and TMC310911. This
      combination will assess the potential pharmacokinetic enhancement (boosting) on the latter
      compound. TMC558445 is to be used as a booster for TMC310911. The trial consists of 2 parts:
      a single dose escalation and a multiple dose escalation part. The single dose escalation part
      will consist of 6 sessions. The single dose part will include 18 healthy adult volunteers,
      divided over 2 panels. In each session, 6 healthy volunteers will receive TMC558445 and 3
      healthy volunteers will receive placebo with standard meals. Intake of TMC558445/placebo will
      take place on Day 1 of each session between 07:00 and 11:00 a.m. Single doses of 40, 100,
      200, 400, 800, and 1600 mg of TMC558445/placebo will be administered alternating over the 2
      panels. The trial will be stopped earlier when the maximum tolerated dose is reached. A
      washout period (a period where no treatment will be taken in view of having all the
      medication eliminated from the body before starting a new treatment) of at least 10 days will
      be respected between consecutive TMC558445/placebo dosings. Once, a food effect will be
      studied under fasted conditions at one of the previously studied doses. The multiple dose
      escalation part of this trial will start when the 200 mg dose is found to be safe.This part
      of the trial will include 27 healthy adult volunteers, divided over 3 panels: 6 will receive
      TMC558445 and 3 will receive placebo. TMC558445/placebo will be administered during 7
      consecutive days. The treatment will be twice daily between 07:00 and 11:00 a.m. and between
      07:00 and 11:00 p.m. Volunteers will receive a single oral dose of 300 mg of TMC310911 on Day
      7 and on Day 1 of Session XI (after a washout period of at least 14 days). Dose escalation in
      the single and multiple ascending dose regimens will continue only if the previous dose was
      found safe. Pharmacokinetic profiles of TMC558445 will be determined up to a max of 72 h
      after the last intake per session. Pharmacokinetic profiles of TMC310911 will be determined
      over 24 h. The expected duration of the investigational period in the single escalation dose
      part is at least 8 weeks and at least 3 weeks in the multiple escalation dose part. Safety
      and tolerability evaluations will be recorded at regular intervals throughout the trial.
      Blood and urine samples will be taken at predefined timings as well as ECG measurements,
      vital signs (blood pressure and heart rate), and physical examinations. The study has been
      amended. In Panel 5, TMC558445 may now be administered either twice daily or once daily and
      TMC310911 may be given at a 300 mg or 600 mg single dose. Decision on dosing regimen,
      TMC310911 dose and food conditions will be made based on results of the previous panels.

      The study has been amended as follows:

      Panel 6 (9 adult volunteers), will receive 800 mg Darunavir (DRV) on day 7 combined with
      TMC55844 that has been given for 7 days at 200 mg once daily dosis. After a wash out period
      of 14 days the participants will receive Darunavir 800 mg alone. TMC558445, TMC310911 or
      placebo will be formulated as oral drinkable solution. Part 1 will consist of single dose
      TMC558445/placebo from 40 up to 1600mg on Day 1 of each session with a volume between 2 and
      20ml. Part 2 will consist of TMC558445/placebo twice daily from Day 1 to Day 7 with max dose
      of 200mg and volume of 5 ml + a single intake of 300 or 600mg TMC310911(12/24ml)/ DRV 800mg
      on morning of Day 7 in one session and single dose of TMC310911/ DRV on Day 1 in the second
      session.
    

Intervention name(s): TMC558445; TMC310911; Darunavir; Placebo
Intervention type(s): Drug
Intervention MeSH terms: Darunavir; TMC-310911
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: PEPI-TiDP23-C103; PEPI-C103; PEPI; TMC558445; TMC310911; Darunavir, Healthy volunteers; Pharmacokinetics; HIV Infections