A Study to Evaluate the Pharmacokinetics, Safety, Tolerability, and Antiviral Efficacy of TMC278 in Human Immunodeficiency Virus Infected Adolescents

• Pharmacokinetics of TMC278 as measured by maximum plasma concentration (Cmax) [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
  
• Pharmacokinetics of TMC278 as measured by area under the plasma concentration curve (AUC24) [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
  AUC24 is defined area under the plasma concentration time curve from 0 to 24 hours post dosing of TMC278.
  
  
• Pharmacokinetics of TMC278 as measured by time to reach the maximum plasma concentration (tmax) [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
  

• Number of patients with adverse events (part 1 and part 2) [ Time Frame: Up to 244 weeks (including 4 week follow up visit) ] [ Designated as safety issue: No ]
  Safety measures include adverse events, vital signs, physical examination, hematology, biochemistry and electrocardiogram
  
  
• Change in CD4+ cells and viral load (part 2) [ Time Frame: Screening (2 months prior to treatment) to Week 240 ] [ Designated as safety issue: No ]
  Change in the CD4+ cells will evaluate immunologic changes at week 24 and 48 weeks of treatment with TMC278
  
  
• Evolution of viral genotype and phenotype (part 2) [ Time Frame: Up to post Week 48 extension (Week 240) ] [ Designated as safety issue: No ]
  This endpoint is measured at 24 and 48 weeks of treatment with TMC278.
  
  
• Treatment adherence as measured by the Study Adherence Questionnaire (part 2) [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
  This endpoint is measured by Study Adherence Questionnaire for children and teenagers. The adherence questionnaire should be completed by by the patient. Ths questionnaire includes questions about the medicine, it's color and dosage.
  
  
• Assessment of pharmacokinetic-pharmacodynamic relationships [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
  This endpoint evaluates pharmacokinetic-pharmacodynamic relationships for safety and efficacy of TMC278
  
  

This is a 48-week, Phase II, open-label (all people involved know the identity of the assigned drug) and single arm study. The study will consist of a screening period of maximum 6 weeks, a treatment period of maximum 48 weeks, and a 4 week follow-up period taking place regardless of the presence of serious adverse events (SAEs) if patients withdraw early (ie, before Week 48) or if patients do not participate in the extension after Week 48; also after Week 48, a 4-week follow-up visit is only required in case of ongoing SAEs at the final on treatment visit. The initial 48-week treatment period will be structured into 2 parts. The first part includes part 1a and part 1b. The first part of the trial is designed to evaluate the steady-state pharmacokinetic (PK) profile and the short-term safety and antiviral activity of TMC278 25 mg once daily when administered in combination with 2 NRTIs, in adolescents. At Week 2/4, intensive PK will be done and an analysis together with short-term safety and antiviral activity will be reviewed by a data monitoring committee (DMC). If the mean steady-state exposure in this first group of patients is comparable to that of the adult population (ie, is within 80-125 percentage of the mean exposure of the 25 mg once daily dose group in study, TMC278-C204), and the Week 2 safety and antiviral activity results have been reviewed and deemed satisfactory by the DMC, the second part of the trial will start. Week 12 interim analysis will be performed when all Part 1a and Part 1b patients have reached 12 weeks of treatment or discontinued earlier. If the mean exposure in adolescents is greater than 125 percentage of the mean exposure in adults, but antiviral activity results are satisfactory and there are no safety concerns, as judged by the DMC, the second part of the trial will start. If the mean exposure in adolescents is greater than 125 percentage of the mean exposure in adults, the antiviral activity is satisfactory, but there are safety concerns that potentially could be avoided by a lower exposure to TMC278, as judged by the IDMC, patients up to a certain body weight (determined based on the intensive PKresults) will be switched to a lower, weight adjusted dose of TMC278. However, if the mean exposure in adolescents is less than 80 percentage of the mean exposure in adults or the Week 2 results are not deemed satisfactory, all patients will be seen for a withdrawal visit, treatment with TMC278 will be stopped, patients will be switched to a locally available ARV regimen, and the trial will be stopped. The second part of the trial will evaluate long-term (48 weeks) safety, efficacy, and pharmacokinetics of TMC278 in combination with the background regimen of 2 NRTIs with a primary analysis time point at 24 weeks. In both parts of the trial, the ART will consist of TMC278 25 mg once daily and an investigator-selected background regimen containing 2 NRTIs. Patients safety will be monitored through out the study and during the follow up visits.