The purpose of this study is to determine the antiviral activity, safety and tolerability of TMC114, formulated as an oral tablet, and administered with a low dose of ritonavir
Primary Outcome Measures:
- The primary objective of the trial is to compare all TMC114/RTV dose groups with control at Week 24 (the primary endpoint) by means of the confirmed virologic response, defined as a drop in viral load of at least 1 log10 versus baseline.
Secondary Outcome Measures:
- To evaluate safety and tolerability over 24 to 144 weeks; To evaluate the durability of the antiviral activity; To investigate the dose-response by comparing the different TMC114/RTV dosages.
| Study Start Date:
| Study Completion Date:
| Primary Completion Date:
||February 2005 (Final data collection date for primary outcome measure)
This trial consists of two parts: a partially blinded dose-finding part followed by an open-label part with the recommended dose of TMC114/RTV. The dose-finding part of this trial consisted of a randomized controlled (standard of care), partially blinded, Phase II trial to determine the antiviral activity, safety and tolerability of TMC114, formulated as an oral tablet, and administered with a low dose of ritonavir. The pharmacokinetics of TMC114 are also assessed.Three hundred HIV-1 infected patients who were three-class-experienced and who were on a stable PI-containing regimen at screening for at least 8 weeks and who had plasma HIV-1 RNA > 1000 copies/mL were eligible. Three-class experience was defined as prior treatment with ³ 2 NRTIs for at least 3 months in total and ³ 1 NNRTI as part of a failing regimen. In addition, patients had to have received at least one PI for at least 3 months in the past and had to have at least 1 primary PI mutation (according to IAS definitions) at screening.As soon as all results to determine eligibility were available, and no later than 2 weeks prior to the baseline visit, the patients were randomized to one of 4 TMC114/RTV treatment groups or to a control group (standard of care). At baseline, patients changed to an investigator selected PI(s) regimen or TMC114/RTV plus optimized background regimen (OBR) consisting of NRTIs with or without T-20.In the dose-finding part of the trial, the primary objective of the trial was to evaluate the dose-response relationship in antiviral activity between the TMC114 /RTV treatment groups at 24 weeks. The recommended dose has been selected based on two joint interim analyses of this trial and of a similar trial (TMC114-C202, conducted in the United States of America, Puerto Rico, and Argentina) including approximately 150 patients in each of the two dose-finding trials (TMC114-C202 + TMC114-C213) who reached Weeks 16 and 24 or dropped out earlier. The Week 24 interim analysis included a total of 497 patients, of whom 329 had reached Week 24 or discontinued earlier. Based on the results of these two joint interim analyses, TMC114/RTV 600/100 mg b.i.d. was selected as the recommended dose for the open-label part of this trial and for future trials in treatment-experienced HIV-1 infected patients. The recommended dose of TMC114/RTV was not communicated to the investigators until the data cut-off date for the primary efficacy analysis of the two dose-finding trials was reached.The primary efficacy analysis was performed when approximately 300 patients in this trial reached 24 weeks of treatment or discontinued earlier (i.e., the primary endpoint, which was reached on 1 February 2005; A total of 318 patients were included in the analysis of whom 301 reached Week 24 or discontinued earlier). In this primary efficacy analysis, all TMC114 groups were compared to the control group by means of the confirmed virologic response at Week 24, defined as a drop in viral load of at least 1 log10 versus baseline. This primary efficacy analysis confirmed that TMC114/RTV 600/100 mg b.i.d. is the recommended dose for treatment-experienced HIV-1 infected patients.After the primary endpoint of the trial was reached (1 February 2005), and after approval of the related protocol amendment by the relevant IEC/IRB and authorities, the patients in the TMC114/RTV groups were instructed to switch to the recommended dose of TMC114/RTV (600/100 mg b.i.d.) in the open-label part of the trial.In addition, long term safety, tolerability and the durability of antiviral activity of TMC114/RTV over 144 weeks in 3-class-experienced HIV-1 infected patients will be evaluated. The trial includes a screening period of a maximum of 6 weeks, and a 144-week treatment period followed by a 4-week follow-up period. The maximum duration of the trial will be 154 weeks.Tibotec will provide follow-up treatment with TMC114/RTV for all patients who continue to benefit from treatment with TMC114/RTV. TMC114 will be provided until the drug is commercially available or until its development is discontinued.The patient will remain on the study until he/she no longer benefits from TMC114/RTV, as judged by the investigator, or he/she meets one of the withdrawal criteria. Dose-finding part of the trial: 400 mg/100 mg q.d. TMC114/RTV or 800 mg/100 mg q.d. TMC114/RTV or 400 mg/100 mg b.i.d. TMC114/RTV or 600 mg/100 mg b.i.d. TMC114/RTV. Open-label part of the trial: 600 mg/100 mg b.i.d. TMC114/RTV. Total treatment duration of 144 weeks.