| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 primary objective is to demonstrate non-inferiority in virologic response (time to loss of virologic response (TLOVR)), defined as a confirmed plasma viral load of less than 50 copies/mL, with TMC114/RTV versus LPV/RTV treatment at 48 weeks, when administered in combination with a fixed background regimen, consisting of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). |
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| E.2.2 | Secondary objectives of the trial |
- to evaluate safety and tolerability over 96 weeks
- to evaluate the durability of virologic response over 96 weeks
- to compare the immunologic response
- to evaluate the pharmacokinetic/pharmacodynamic relationship
- to evaluate the superiority for virologic response in case TMC114 is non-inferior
- to evaluate the resistance characteristics
- to determine and compare the subject-reported health status, well-being, the degree of distress caused by symptoms and the adherence to the ARV medication in subjects treated with TMC114/RTV and LPV/RTV, in combination with TDF/FTC
- to evaluate health economic objectives
- to monitor potential body changes through anthropomorphic measurement
- to assess the population pharmacokinetics of TMC114 in this treatment-naïve population
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| 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. Male or female aged 18 years or older.
2. Subjects with documented HIV-1 infection.
3. Screening plasma HIV-1 RNA ≥ 5000 copies/mL.
4. Subjects qualify for treatment initiation based on the investigator's assessments and/or according to treatment guidelines.
Note: Most current treatment guidelines recommend considering initiation of ART when CD4 cell counts are below 350 cells/µL. However, clinical situations may warrant initiating ART with CD4 cell counts above 350 cells/µL. Examples of such situations would include rapidly declining CD4 cell counts over time, high plasma viral load, history of AIDS-defining illnesses or severe symptoms of HIV infection.
5. Subjects have voluntarily signed the informed consent form.
6. Subjects can comply with the protocol requirements.
7. General medical condition, in the investigator’s opinion, does not interfere with the assessments and the completion of the trial.
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| E.4 | Principal exclusion criteria |
Subjects meeting one or more of the following criteria cannot be selected.
1. Presence of any currently active AIDS defining illness (Category C conditions according to the CDC Classification System for HIV Infection 1993) with the following exceptions:
- Stable cutaneous Kaposi’s Sarcoma (i.e., no internal organ involvement other than oral lesions) that is unlikely to require any form of systemic therapy during the trial time period.
- Wasting syndrome.
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 case the medication used is not part of the disallowed medication.
2. Any condition (including but not limited to alcohol and drug use), which, in the opinion of the investigator, could compromise the subject's safety or adherence to the trial protocol.
3. Previous or current use of ARVs (including both investigational as well as commercially available ARVs indicated for the treatment of HIV-infection and ARVs for treatment of hepatitis B infection with anti-HIV activity (e.g., adefovir, lamivudine, emtricitabine)).
Note: Women who used nevirapine to prevent mother-to-child transmission (MTCT) are allowed in the trial, as long as they have never received other ARVs. Women who used zidovudine to prevent MTCT will not be allowed as this may result in reduced susceptibility to the fixed background regimen.
Note: Subjects treated for postexposure prophylaxis will not be allowed.
4. Treatment for primary HIV infection.
5. Use of any non-ARV investigational agents within 90 days prior to screening.
6. Use of disallowed concomitant therapy.
7. Life expectancy of less than 6 months.
8. Pregnant or breast-feeding.
9. Female subject of childbearing potential without use of effective non-hormonal birth control methods or not willing to continue practicing these birth control methods for at least 30 days after the end of the treatment period.
Note: Hormonal based contraception may not be reliable when taking TMC114, therefore to be eligible for this trial women of childbearing potential should either:
(1) use a double barrier method to prevent pregnancy (i.e., use a condom with either diaphragm or cervical cap), or,
(2) use hormonal based contraceptives in combination with a barrier contraceptive (i.e., male condom, diaphragm or cervical cap or female condom), or,
(3) use an intra uterine device (IUD) in combination with a barrier contraceptive (i.e., male condom, diaphragm or cervical cap or female condom), or,
(4) be non-heterosexually active, practice sexual abstinence or have a vasectomized partner (confirmed sterile).
Note: Women who are postmenopausal for at least 2 years, women with total hysterectomy and women with tubal ligation are considered of non-childbearing potential.
10. Subjects with clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (liver insuffiency).
Note: Subjects co-infected with chronic hepatitis B or C will be allowed to enter the trial if their condition is clinically stable and is not expected to require treatment during the trial period. Subjects diagnosed with acute viral hepatitis at screening will not be allowed in the trial.
Please refer to the package insert with respect to proper care of hepatitis B co-infection as TDF (300 mg) and FTC (200 mg) are included in the fixed background regimen.
11. Any active clinically significant disease (e.g., cardiac dysfunction, pancreatitis, acute viral infections) or findings during screening of medical history or physical examination that are expected to compromise the subject's safety or outcome in the trial.
12. Subjects with a grade 3 or 4 laboratory abnormality as defined by DAIDS grading scheme, with the following exceptions unless clinical assessment foresees an immediate health risk to the subject:
· Subjects with pre-existing diabetes or with asymptomatic glucose grade 3 or 4 elevations.
· Subjects with asymptomatic triglyceride or cholesterol elevations of grade 3 or 4.
Note: Re-testing of abnormal screening values that lead to exclusion will be allowed only once using an unscheduled visit.
13. Subjects with calculated creatinine clearance (CLCr) < 70 mL/min.
14. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication (TMC114) or to RTV, LPV, TDF or FTC.
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.
15. Participation in other investigational or cohort trials without prior approval of the sponsor.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Demonstration of non-inferiority in efficacy of TMC114/ritonavir versus lopinavir/ritonavir. |
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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 | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, resistance characteristics |
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| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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 |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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