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 of the trial is to evaluate the antiviral activity of TMC125 800 mg b.i.d. (formulation TF035) and after the formulation switch, 200 mg b.i.d. (formulation F060) as part of an ART containing 2 NRTIs, by evaluating the proportion of subjects with plasma HIV-1 RNA levels < 50 copies/mL at 24 weeks. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives over the treatment period are: - To evaluate the antiviral activity over the treatment period with TMC125; - To evaluate safety and tolerability over the treatment period with TMC125; - To evaluate immunologic changes (as measured by CD4 and CD8 cells) over the treatment period; - To evaluate changes in viral genotype and drug susceptibility during the trial; - To evaluate the efficacy, safety and tolerability of TMC125 compared with the active control group over the treatment period; - To investigate the population pharmacokinetics of TMC125. - to evaluate the durability of efficacy
The objective of the pharmacokinetic sub-study is: - To evaluate the pharmacokinetics of TMC125 in HIV-1 infected subjects at 800 mg (formulation TF035) and 200 mg (formulation F060) b.i.d.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Voluntarily signed informed consent; 2. Documented HIV-1 infection; 3. Male or female subjects, aged above 18 years; 4. Subject can comply with the protocol requirements; 5. Subject: - is currently on a treatment interruption (minimum duration of 4 weeks) at screening and agreeing to remain without ART until baseline OR - is currently receiving a stable (minimum duration of 12 weeks) NNRTI-containing ART at screening and agreeing to stay on that ART until baseline Note: These subjects must be virologically-failing on this first-line NNRTI-containing regimen as documented by a detectable HIV-1 plasma viral load measurement tested locally, prior to and consecutive with the screening sample; OR - has been treated with an NNRTI, either alone or with other ARVs, for prevention of MTCT Note: Subjects treated with an NNRTI-containing regimen for prevention of MTCT are allowed in the trial, however, this subject population will be limited to 25% of the total number of subjects; 6. HIV-1 plasma viral load at screening visit is greater than 1000 HIV-1 RNA copies/mL [assayed by RNA polymerase chain reaction (PCR) ultrasensitive specimen procedure, Roche Amplicor HIV-1 MonitorTM (version 1.5)]; 7. NNRTI-experienced with documented genotypic evidence of resistance to currently available NNRTIs either present at screening or from prior genotypic analysis available in the source documents and after agreement with the sponsor to enroll the subject based on these historical data. A minimum of 1 of the following NNRTI- associated mutations should be present based on the IAS-USA Drug Resistance Mutation Guidelines. A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106M V108I Y181C Y181I Y181V Y188C Y188H Y188L G190A G190E G190S P225H M230L P236L K238N K238T Y318F 8. Subject should be sensitive on the virco®TYPE HIV-1 for the 2 NRTIs to be used in the underlying ART. 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 was randomized to the TMC125 treatment group, has completed the entire 48-week treatment period and has voluntarily agreed to participate. 2. The subject has an undetectable plasma viral load level at Week 40 of the initial trial (<50 copies/mL); in case a subject has a detectable plasma viral load level at Week 40 of the initial trial after being undetectable before, a confirmatory plasma viral load assessment can be performed within 2 weeks after the Week 40 visit. 3. The subject is willing to continue treatment with TMC125 and the same 2 NRTIs as used during the first 48 weeks of treatment in trial TMC125-C227. 4. The subject is willing to comply with the protocol requirements and cooperate with the investigator.
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E.4 | Principal exclusion criteria |
1. Previous treatment with PIs; 2. Previous treatment with a regimen containing only NRTIs. Subjects may have been treated with NRTIs for the prevention of MTCT; 3. Use of disallowed concomitant therapy during the 14 days prior to the start of the treatment period; 4. History of, or currently active, alcohol or drug use that in the investigator’s opinion would likely compromise the subject’s safety and/or compliance with the trial procedures; 5. Life expectancy less than 6 months; 6. Subject currently having any active AIDS defining illness with the following exceptions: - Stable, cutaneous Kaposi’s Sarcoma that is considered at screening unlikely to require any form of systemic therapy during the trial period; -Wasting syndrome due to HIV infection if, it is not actively progressive and its treatment does not require hospitalization or compromise the subject’s safety or ability to adhere to the trial protocol procedures. If subjects are on maintenance therapy for previously diagnosed wasting, they may be eligible for the trial only if such treatment is not included in the list of disallowed medications. 7. Any active clinically significant disease or findings during screening of medical history or physical examination that would compromise the outcome of the trial; 8. Receipt of any investigational drug within 30 days prior to the trial drug administration (except for tenofovir and emtricitabine, which are allowed); 9. Previous permanent discontinuation of any NNRTI due to cutaneous events; 10.Previously demonstrated clinically significant allergy or hypersensitivity to any of the components of the investigational medication; 11.Pregnant or breastfeeding female; 12.Female of childbearing potential without the use of effective birth control methods, or not willing to continue practicing these birth control methods during the trial and for at least 14 days after the end of the trial (or after last intake of ART). Note: Hormonal based contraception may not be reliable when taking TMC125, therefore to be eligible for this trial women of childbearing potential should either: i. use a double barrier method to prevent pregnancy OR ii. Use hormonal based contraceptives in combination with a barrier contraceptive OR iii. Use an intrauterine device (IUD) in combination with a barrier contraceptive OR iv. Be non-heterosexually active, practice sexual abstinence, or have a vasectomized partner. Note: women who are post-menopausal for at least 2 years, women with total hysterectomy and women who have had a tubal ligation are considered of non-childbearing potential. 13. Renal impairment as defined by serum creatinine > 2 x the upper limit of normal (ULN); 14. Any grade 3 or grade 4 toxicity according to the ACTG grading severity list [except for grade 3 glucose, asymptomatic triglyceride/cholesterol grade 3 or 4 elevations, isolated grade 3 increases in gamma-glutamyl transferase (GGT) or isolated grade 3 increases in amylase with no increase in lipase and no history of pancreatitis]; 15.Acute hepatitis A, B or C; 16.Chronic hepatitis B or C with aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 x ULN; 17.Subjects with clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels [e.g., International Normalized Ratio (INR) > 1.3 or albumin < 30 g/l or bilirubin > 2.5 x ULN] 18.Subjects who have been randomized to a TMC125 and/or TMC120 and/or R278474 treatment group in a previous trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy parameter is the proportion of subjects with undetectable plasma viral load values (< 50 copies/mL) at week 24. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
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 |
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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) | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
TMC125 (800mg bid) added to 2 inv. sel. NRTIs is comp. to inv. sel. comb. therapy of 1PI and 2 NRTIs |
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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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |