| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 6.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020161 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The Part I main objectives are - To evaluate the pharmacokinetic profile of two different doses of TMC114 in combination with low-dose ritonavir administered b.i.d. in the pediatric population at steady-state AUC12h, Cmax and Cmin; - To provide dose recommendation of TMC114 per body weight in pediatric subjects of 8805; 20 kg to 50 kg; - To evaluate short-term safety, tolerability and antiviral activity of two different doses of TMC114/rtv administered b.i.d. in treatment-experienced pediatric subjects. Part II Primary Objective - To evaluate long-term safety, tolerability and efficacy of TMC114 in combination with low-dose ritonavir administered b.i.d. and other ARV agents over a 24-week treatment period at the recommended pediatric 8805; 20 kg to 50 kg and adult 8805; 50 kg doses. |
|
| E.2.2 | Secondary objectives of the trial |
| Part II Secondary Objectives - To evaluate long-term safety, tolerability and efficacy of TMC114 in combination with low-dose ritonavir administered b.i.d. and other ARV agents over a 48-week treatment period at the recommended pediatric 8805; 20 kg to 50 kg and adult 8805; 50 kg doses; - To evaluate immunology, resistance characteristics, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic PD relationships of TMC114/rtv over 48 weeks of treatment. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
| Subjects who meet all of the following criteria are eligible for this trial. 1. Boys and girls, aged between 6 and 17 years. 2. Subjects with documented HIV-1 infection. 3. Body weight Part I 8805; 20 to 50 kg. Body weight Part II 8805; 50 kg and from 8805; 20 to 50 kg after pediatric dose selection. 4. Being able to swallow the TMC114 tablet formulation s and the ritonavir capsule formulation, and to tolerate the ritonavir liquid formulation liquid formulation only applicable for subjects 40 kg . 5. Stable CD4 percentage no more than 5 decrease in CD4 percentage between the screening visit and the last available CD4 measurement with a minimum of 4 weeks and a maximum of 24 weeks between screening visit and last measurement . 6. Subjects currently on a stable ART who need to change their ARV regimen because it is currently failing at least 12 weeks on therapy , with a viral load of 1000 copies/mL. 7. Parents or legal representative and trial subjects where appropriate, depending on age and local regulation willing and able to give consent. Children will be informed about the trial, and asked to give positive assent as per description in Chapter II, Section 6.4. 8. Subjects can comply with the protocol requirements. 9. General medical condition, in the investigator s opinion, does not interfere with the assessments and the completion of the trial. 10. Female subjects who are sexually active and able to become pregnant must use a safe and effective birth control method, such as sexual abstinence or medically accepted barrier methods of contraception e.g., diaphragm, and condom during the study. Hormonal birth control alone would not be considered adequate, as the interaction between study drug and hormonal birth control is not available |
|
| E.4 | Principal exclusion criteria |
| Subjects meeting one or more of the following criteria cannot be selected. 1. Part I Use of the NNRTI efavirenz as part of the current regimen is not allowed. Part II Use of efavirenz as part of the current regimen is allowed see Table 2 . 2. Presence of any currently active AIDS defining illness Category C conditions according to the CDC Classification System for HIV Infection 1993 or according to the 1994 revised CDC Classification System for HIV infection in children less than 13 years of age see Addendum 6; Section 7.6 Note An AIDS defining illness not clinically stabilized for at least 30 days will be considered as currently active. Note Primary and secondary prophylaxis for an AIDS defining illness is allowed in cases where the medication administered is not part of the disallowed medications see Section 5.5.12 . 3. Active substance use as determined by the investigator during anamnesis that includes but is not limited to daily or frequent alcohol intake, use of solvents, barbiturate, amphetamine, and recreational or narcotic drugs. Note Prescribed use of methadone is allowed see Table 2 . 4. Use of disallowed concomitant therapy see Section 5.5.12 . 5. Use of any antiretroviral and non-antiretroviral investigational agents within 30 days prior to screening, except for tenofovir, tipranavir, atazanavir and fosamprenavir. Note TMC114 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 Day 1 . 6. Life expectancy of less than 6 months. 7. Co-enrollment in other clinical and/or cohort trials without written permission of the sponsor. 8. Pregnancy or breastfeeding. 9. Any active clinically significant disease e.g., 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. 10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication TMC114 or ritonavir. Note TMC114 is a sulfonamide. Subjects who previously experienced a sulfonamide allergy will be allowed to enter the trial. To date, no potential for cross sensitivity between drugs in the sulfonamide class and TMC114 has been identified in subjects participating in phase II trials. 11. Subjects with documented hepatic impairment. Note subjects co-infected with chronic hepatitis B or C determined by hepatitis B surface antigen, anti core-hepatitis B IgG antibody and hepatitis C antibody will be allowed to enter the trial if their condition is clinically stable, and they are not expected to require treatment during the study period and have ALT or AST levels 3 x ULN. Subjects diagnosed with acute viral hepatitis at screening will not be allowed in the trial e.g., hepatitis A IgM antibody . 12. Subjects with the following laboratory abnormalities as defined by the DAIDS grading scheme any grade 3 or 4 toxicity with the following exceptions unless clinical assessment foresees an immediate health risk to the subject - subjects with pre-existing diabetes or asymptomatic glucose elevations of grade 3 or grade 4 - subjects with asymptomatic triglyceride or cholesterol elevations of grade 3 or 4. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| For Part I The primary efficacy parameter will be virologic response at Week 2, defined as a drop in viral load copies/mL of at least 0.5 log10 versus baseline. The main analysis will be a noncompleting failure analysis NC F ; i.e. all subjects who have discontinued the trial prematurely will be considered as failures. For Part II The primary efficacy parameter will be confirmed virologic response TLOVR at Week 24, defined as a drop in viral load copies/mL of at least 1 log10 versus baseline. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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