| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 |
PART I OBJECTIVES
The 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 ≥ 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 (≥ 20 kg to < 50 kg) and adult (≥ 50 kg) doses. |
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| 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 (≥ 20 kg to < 50 kg) and adult (≥ 50 kg) doses;
- To evaluate immunology, resistance characteristics, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic (PD) relationships of TMC114/rtv over 48 weeks of treatment.
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| E.2.3 | Trial contains a sub-study | No |
| 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: ≥ 20 to < 50 kg.
Body weight Part II: ≥ 50 kg and from ≥ 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 first, second or third line ART who need to change their ARV regimen to a boosted-PI based regimen because it is currently failing, with a viral load of > 1000 copies/mL (minimum required viral load level to obtain a reliable genotype test).
Note: Current failing ART is defined after at least 12 weeks on therapy if one of the following situations occurs:
1) Less than 1.0 log10 drop from baseline in HIV RNA levels in children or adolescents on ART
2) HIV RNA not suppressed to undetectable levels after 4-6 months in children or adolescents on ART
3) Repeated detection of HIV RNA in children or adolescents who initially had undetectable levels on ART
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.
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| 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) |
| To evaluate the pharmacokinetics profile on day 14 of two different doses of TMC114 in combination with ritonavir in the pediatric population at steady-state and to provide dose recommendation of TMC114 per body weight in pediatric patients |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
| To evaluate long-term safety, tolerability and efficacy of TMC114 in combination with low dose ritonavir administered twice daily. and other ARV agents over a 48-week treatment period at the recommended pediatric and adult doses |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability / Dose recommendation in pediatric subjects / Immunology |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| South Africa |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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