TMC114-TiDP29-C228 - A Safety Study to Evaluate the Antiviral Activity of Darunavir (DRV) in Combination With Ritonavir (Rtv) in HIV 1 Infected Children From 3 Years to Below 6 Years of Age

• To evaluate long-term safety, tolerability and efficacy of DRV/rtv administered b.i.d. with other ARV agents over a 48-week treatment period at the recommended dose for HIV-1 infected children aged from 3 years to < 6 years [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• To evaluate immunology, resistance characteristics, pharmacokinetics, and pharmacokinetic/pharmacodynamic (PK/PD) relationships over 48 weeks of treatment. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

• To evaluate long-term safety, tolerability and efficacy of DRV/rtv administered b.i.d. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• To evaluate immunology, resistance characteristics, pharmacokinetics, and pharmacokinetic/pharmacodynamic (PK/PD) relationships over 48 weeks of treatment [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

The purpose of this Phase II trial is to evaluate the pharmacokinetics (blood levels), safety and antiviral activity to support dose recommendations by body weight of darunavir with low-dose ritonavir (DRV/rtv), in combination with other antiretroviral drugs (ARVs), in treatment-experienced HIV 1 infected children aged from 3 years to < 6 years and weighing between 10 kg and < 20 kg .

TMC114-C228 is an open-label, Phase II trial to evaluate the pharmacokinetics, safety and antiviral activity to support dose recommendations by body weight of darunavir/ ritonavir (DRV/rtv), in combination with other antiretroviral drugs (ARVs), in treatment-experienced human immunodeficiency virus type 1 (HIV-1) infected children aged from 3 years to < 6 years and weighing between 10 kg and < 20 kg. In addition, efficacy, safety and tolerability of DRV/rtv will be evaluated in combination with other ARVs over a 48-week treatment period. Approximately 24 male and female HIV-1 infected children, who are on a stable ARV treatment for at least 12 weeks but need to change their ARV regimen because it is currently failing (plasma viral load > 1000 copies/mL) and have < 3 DRV resistance-associated mutations (RAMs), will be included in the trial for each of the two following weight bands: 10 kg to < 15 kg and 15 kg to < 20 kg. Priority will be given to have at least 10 patients recruited in the lowest weight band. To ensure that children across the two weight bands will be enrolled, a minimum of 10 and a maximum of 14 children per weight band will be recruited. Once the required number of children are recruited in at least one of the weight bands, recruitment will be closed for that specific weight band. Trial sites will be informed in advance regarding stop of recruitment. Investigators should identify eligible children in advance in order to ensure the shortest possible recruitment period. For this reason, recruitment may only start when sufficient numbers sites participating have the necessary documentation and approvals in place and are therefore considered activated for enrolment. Patients will receive DRV/rtv according to their body weight: DRV (oral suspension) 20 mg/kg in combination with rtv (oral solution) 2.6-3.2 mg/kg will be administered b.i.d.(twice daily) together with an OBR (optimized background regimen) consisting of 2 active ARVs with dose recommendations in pediatrics. Patients will receive their first intake of trial medication at the study center and will stay in the day clinic/hospital on Day 1 to assess initial safety and tolerability of their new treatment (overnight hospitalization is allowed). The ARVs in the OBR should be selected based on the results of resistance testing performed at screening and the child's ARV history. Single substitutions of ARVs in the OBR are allowed for tolerability/toxicity reasons. The first 2 weeks of the trial are designed to support dose recommendations of DRV/rtv in this patient population. At Week 2, pharmacokinetic assessments will be performed. Sampling will occur at 5 different time points on Day 14 (Week 2), on which day some centers may consider it appropriate for patients to stay in the clinic overnight. In case recruitment of the 24 children takes more than 12 weeks, a Week 2 analysis can be performed on the data of the first 12 children. Once Week 2 (Day 14) assessments are available for all patients, the DSMB (Drug Safety Monitoring board) will review all available pharmacokinetics, safety and antiviral activity data, in order to support DRV/rtv dose recommendations. Communication on the outcome of the DSMB meeting will be sent to all sites and IECs/IRBs.If the results of the Week 2 pharmacokinetic analysis show that target DRV exposure is not achieved, the DRV dose will be adjusted and 2 weeks after dose adjustment an additional PK visit will be scheduled at which 2 plasma samples will be drawn (one predose of the DRV/rtv morning intake in the clinic and one sample at least one hour after the fist sample was taken and after DRV/rtv intake) for pharmacokinetic assessments. If the DRV dose will need to be adjusted, either a dose-adjustment visit or an additional PK visit thereafter can be combined with visits according to the main flowchart, if these 2 visits fall within 2 weeks. Once these new PK assessments become available for all subjects, the DSMB will review again all available pharmacokinetics, safety and antiviral activity data in order to support the new DRV/rtv dose recommendations. (Note: The DRV/rtv dose will not exceed the recommended dose for treatment-experienced HIV-1 infected adults.) Patients will continue treatment with DRV/rtv in combination with an OBR for 48 weeks to evaluate safety, tolerability and efficacy of DRV/rtv at the selected pediatric dose in this population. The trial will consist of a screening period of 4 weeks, a 48-week treatment period, followed by a 4-week follow-up (FU) period. Safety, efficacy, resistance, pharmacokinetic and PK/PD analyses will be performed at Week 24 (primary analysis when all patients have been treated for 24 weeks or discontinued earlier) and Week 48 (final analysis; when all patients have been treated for 48 weeks or discontinued earlier). During the trial, the patient will be seen at regular visits during which the investigator will assess the patient's medical condition, any AEs and study drug compliance. Laboratory evaluations for efficacy and safety will be done at regular visits. The DSMB, composed of external experts and Sponsor representatives not directly involved in trial conduct, will also be responsible for regular monitoring and objective assessment of the safety.The primary efficacy endpoint will be a plasma viral load < 50 copies/mL at Week 24. Resistance determinations will include fold change (FC) in EC50, number of protease (PR) mutations, DRV RAMs, protease inhibitor (PI) RAMs, and primary PI mutations and will be performed at screening (only genotyping), baseline, Week 24, Week 48 and in the event of early withdrawal. Sparse blood sampling will be performed for all patients for assessment of DRV population pharmacokinetics at Weeks 4, 24 and 48 (and in the case of DRV dose adjustment, if applicable, see above). ARV medication adherence and taste testing of DRV will be assessed during the trial by means of questionnaires. Patients may discontinue the trial for lack or loss of response, and patients must be withdrawn if they experience a grade 4 AE or confirmed grade 4 laboratory abnormality considered to be at least possibly related to trial medication. Patients who complete the 48 weeks of treatment with DRV/rtv and who continue to benefit from this treatment, will have the opportunity to continue this treatment until the subject no longer benefits from the drug, until DRV is commercially available or can be accessed from another source (e.g., access program, government program) or until the development program is discontinued. 48-weeks, excluding screening (4 weeks) and post-treatment follow-up (4 weeks). The selected dose of trial medication is:- DRV oral suspension (100 mg/mL): 20 mg b.i.d. (twice daily) per kg body weight, which will be administered by a modified syringe with a scale of 0.2 mL;- Ritonavir oral solution (80 mg/mL): approximately 3 mg (range: 2.6 - 3.2 mg) b.i.d (twice daily) per kg body weight, which will be administered by an insulin syringe.

• Drug: liquid ritonavir
  Oral solution (80 mg/mL): approx 3 mg (range: 2.6-3.2 mg) twice daily for 48 wks
• Drug: Darunavir tablets
  75 mg tablets if weight > 20kg during trial.
• Drug: Darunavir suspension
  Oral suspension (100 mg/mL): 20 mg twice daily per kg body weight for 48 weeks

• Experimental: 001
  Darunavir suspension Oral suspension (100 mg/mL): 20 mg twice daily per kg body weight for 48 weeks
  Intervention: Drug: Darunavir suspension
• Experimental: 002
  liquid ritonavir Oral solution (80 mg/mL): approx 3 mg (range: 2.6-3.2 mg) twice daily for 48 wks
  Intervention: Drug: liquid ritonavir
• Experimental: 003
  Darunavir tablets 75 mg tablets if weight > 20kg during trial.
  Intervention: Drug: Darunavir tablets

Inclusion Criteria:

• Patients with a documented HIV 1 infection (by any of the local standard diagnostic methods, such as HIV PCR-DNA, ELISA or western blot (WB) test for HIV antibodies, etc.)
• Body weight from 10 kg to <20 kg at screening
• Patients currently on stable ART (anti retroviral therapy) for at least 12 weeks, who need to change their ARV regimen because it is currently failing, with a viral load of > 1000 copies/mL
• Screening genotype resistance test results showing < 3 DRV resistance-associated mutations (RAMs)
• Parents or legal representative willing and able to give consent

Exclusion Criteria:

• Patients with presence of any currently active conditions included in the listing of WHO ( World Health Organisation ) Clinical Stage 4 and patients with presence of a non-HIV encephalopathy
• Administration of any ARV (antiretroviral) or non-ARV investigational medication or investigational vaccine within 30 days prior to screening, except for those medications where dose recommendations for children are available (Note: DRV should not be used within 14 days following the use of tipranavir)
• A minimal 14 day washout period is required in which tipranavir must be either interrupted or substituted to an investigator selected PI regimen until the baseline visit
• Co-enrollment in other clinical and/or cohort trials without written permission of the Sponsor
• Any active clinically significant disease (e.g., tuberculosis [TB], cardiac dysfunction, pancreatitis, acute viral infections) or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the subject's safety or outcome of the trial