| 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 | 9.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020192 |
|
| 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 of the trial is to show the superiority of TMC125 compared to placebo as part of an ART containing TMC114/RTV and an investigator-selected OBR, in the proportion of subjects with undetectable plasma viral load values (< 50copies/mL) at Week 24 in treatment-experienced HIV-1 infected subjects. |
|
| E.2.2 | Secondary objectives of the trial |
- to compare the antiviral efficacy of TMC125 to placebo in addition to the ART at all time points
- to compare the safety and tolerability of TMC125 to placebo
- to compare the immunologic changes with TMC125 to placebo
- to evaluate changes in HIV-1 genotype and drug susceptibility
- to evaluate the population pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of TMC125 and TMC114
- to evaluate and test global health status as measured by the Functional Assessment of HIV Infection questionnaire, a patient-reported outcome instrument. The primary PRO objectives are to show the superiority of TMC125 over placebo at Week 24 on the physical well-being subscale, as well as on the functional and global well-being subscale of the FAHI questionnaire.
- to collect medical resource utilization information and use of a preference-based PRO instrument (EuroQol-5 Dimension) to calculate utility values, both of which may be used in future economic evaluation models.
|
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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. Male or female subjects, aged 18 years or above.
2. Subject has signed the ICF voluntarily.
3. Subject can comply with the protocol requirements.
4. Subject with documented HIV-1 infection.
5. HIV-1 plasma viral load at screening visit above 5000 HIV-1 RNA copies/mL (assayed by RNA polymerase chain reaction [PCR] ultrasensitive specimen procedure Roche Amplicor HIV-1 MonitorTM).
6. On a stable ART for at least 8 weeks at Screening, and willing to stay on that treatment until Baseline.
7. Documented genotypic evidence of resistance to currently available NNRTIs by having at least 1 NNRTI resistance-associated mutation present (based upon the following list, adapted from the IAS-USA: A98G, L100I, K101E/P/Q, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179I/F/G, Y181C/I/V, Y188C/H/L, G190A/E/S, P225H, F227C, M230I/L, P236L, K238N/T, Y318F) on the virco®TYPE HIV-1 at Screening or from prior genotypic analysis, evidence of which should be available in the source documents and enrolment of the subject based on these data needs to be agreed upon by the sponsor.
8. Subject has 3 or more documented primary PI mutations (as listed by the most recent IAS-USA list of mutations; currently the list of November 2005 (see addendum 9) which will be updated according to any new published lists) on the
virco®TYPE HIV-1 at Screening.
9. General medical condition, in the investigator’s opinion, does not interfere with the
assessments and the completion of the trial.
Criteria for Entering the Optional Extended Treatment Period
1. The subject has completed the entire 48-week treatment period and has voluntarily
agreed to participate (i.e., has signed the updated ICF).
2. The subject is willing to continue treatment in a blinded fashion with the same OBR
as used during the original 48 weeks of treatment, until the database has been
locked for the 48 week analysis, after which all subjects will be unblinded and can
continue randomized treatment in an open-label fashion.
3. The subject is willing to comply with the protocol requirements and cooperate with
the investigator.
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|
| E.4 | Principal exclusion criteria |
Subjects meeting 1 or more of the following criteria cannot be selected.
1. Primary HIV-1 infection.
2. HIV-2 infection.
3. Use of disallowed concomitant therapy.
4. 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 protocol.
5. Life expectancy less than 6 months according to the judgment of the investigator.
6. Subject has any currently active AIDS defining illness with the following exceptions, which must be discussed with the sponsor prior to enrollment:
· Stable cutaneous Kaposi’s Sarcoma that is unlikely to require any form of systemic therapy during the trial period.
· Wasting syndrome due to HIV infection.
Note: Primary and secondary prophylaxis for an AIDS defining illness is allowed in case the medication used is not part of the disallowed medication.
7. Any active clinically significant disease or findings during screening of medical history or physical examination that, in the investigator’s opinion, would compromise the outcome of the trial.
8. Acute viral hepatitis including but not limited to A, B, or C.
9. Chronic hepatitis B and/or C with aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN).
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..
10. Receipt of an investigational drug within 30 days prior to the trial drug administration, with the exceptions of TMC114 and tipranavir, tenofovir, emitracitabine, or TruvadaÒ where these are not yet licensed in a participating country.
11. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medications administered in this trial.
12. Pregnant or breastfeeding female subject.
13. Female subject of childbearing potential not using effective birth control methods or not willing to continue practicing these birth control methods during the trial and for at least 30 days after the end of the trial (or after last intake of investigational ARVs).
Note: Hormone-based contraception may not be reliable when taking investigational agents; therefore, to be eligible for this trial, women of childbearing potential should either:
(1) use a double barrier method to prevent pregnancy (i.e., using a condom withdiaphragm or cervical cap),
OR
(2) use hormone-based contraceptive in combination with a barrier contraceptive (i.e.,
male condom, diaphragm or cervical cap or female condom),
OR
(3) use an intrauterine device (IUD) in combination with a barrier contraceptive (i.e.,
male condom, diaphragm or cervical cap),
OR
(4) do not engage in heterosexual sex, or have a vasectomized partner with confirmed
sterility.
Note: Women who are postmenopausal for at least 2 years, women with total hysterectomy,
and women who have a tubal ligation are considered of nonchildbearing potential.
Note: Spermacides containing non-oxynol-9 and should not be used as this can potentially
increase the rate of HIV-1 transmission.
Note: Use of an IUD can increase the risk of sexually transmitted infections, including HIV
14. Heterosexually active male subject not using effective birth control methods or not willing to continue practicing these birth control methods during the trial and until 30 days after the end of the trial (or after last intake of investigational ARVs).
15. Any grade 3 or grade 4 toxicity according to the DAIDS grading scale, except for: grade 3 glucose elevation, asymptomatic grade 3 pancreatic amylase elevation, asymptomatic grade 3 triglyceride/cholesterol elevation, asymptomatic grade 4 triglyceride elevation
16. Subject with clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (International Normalized Ratio [INR] > 1.5 or albumin < 30 g/L or bilirubin > 2.5 x ULN).
17. Subjects who previously received treatment with either TMC125, TMC120, or TMC278 in a previous clinical trial.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective is to show superiority of TMC125 over placebo, with respect to
proportion of subjects with undetectable plasma viral load values (<50 copies/mL) calculated according to the TLOVR algorithm at Week 24.
|
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability, superiority of TMC125 compared to placebo, compare immunological changes |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| once the database for the 48-week analysis has been locked: open-label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| 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 | No |
| 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 | 8 |
| 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 | 8 |
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