| 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 | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
|
| 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 dose-response relationship of antiviral activity after 48 weeks treatment with 3 different dose regimens of TMC278. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
- To evaluate antiviral activity between the TMC278 dose regimens over 96 weeks.
- To evaluate antiviral activity of TMC278 mg q.d. from Week 96 onwards
- To evaluate the safety and tolerability of TMC278.
- To compare safety and efficacy of TMC278 with the control group (efavirenz).
- To evaluate immunologic changes (as measured by CD4 and CD8 cells).
- To evaluate changes in viral genotype and drug susceptibility.
- To evaluate the pharmacokinetics of TMC278.
The main objective of the third optional extension phase is to allow continued access to TMC278 to subjects who completed the 240 weeks of treatment with TMC278 in the second open-label extension part of the trial and who continue to benefit from this treatment, and live in a region where TMC278 is not yet commercially available, reimbursed by the public and/or private health system or cannot be accessed from another source (e.g., access program, government program). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A sub-study of TMC278-C204 to evaluate the pharmacokinetic profile of TMC278 at week 4, 24 and optionally (subject's decision) week 48 of different doses of TMC278 as an addition to an investigator-selected combination of 2 NRTIs. (version 1.0, 15 November 2004) |
|
| 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 having documented HIV-1 infection.
3. Subject is willing to sign the informed consent form voluntarily.
4. Cortisol of at least 550 nmol/L (19.9 µg/dL) at least at one of the 3 timepoints (i.e., morning cortisol, 30 or 60 minutes after 250 µg ACTH stimulation) on the screening assessment.
5. Subject can comply with the protocol requirements.
6. HIV-1 plasma viral load at screening visit above 5000 HIV-1 RNA copies/mL (assayed by RNA polymerase chain reaction standard specimen procedure).
7. In the judgement of the investigator, it is appropriate to initiate ARV therapy based on the
subject's clinical condition and taking into account guidelines for the treatment of HIV-1 infection.
8. Subject has never been treated with an ARV drug or therapeutic HIV vaccine, or has received ≤ 2 weeks treatment prior to screening with an NRTI and/or PI.
9. Screening virco®TYPE HIV-1 demonstrates sensitivity to investigator selected nucleosides.
10. Subject agrees not to start ARV before the baseline visit.
11. 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 Open-Label Extention Part I, II:
1. The subject has completed the entire 96-week treatment period and has voluntarily agreed to participate (i.e., has signed the updated ICF).
2. The subject has completed the entire 144-week treatment period and has voluntarily agreed to participate (i.e., has signed the updated ICF).
3. The subject is willing to comply with the protocol requirements and cooperate with the investigator.
Criteria for Entering the Optional Open-Label Extension Part III:
1. The subject has completed the entire 240-week treatment period with TMC278 and has voluntarily agreed to
participate (i.e., has signed the updated ICF).
2. The subject continues to benefit from this treatment.
3. The subject lives in a region where TMC278 is not yet commercially available, reimbursed by the public and/
or private health system or cannot be accessed from another source (e.g., access program, government program). |
|
| E.4 | Principal exclusion criteria |
1. Use of disallowed conc. therapy
2. History of or currently active alcohol or drug use which will likely compromise subjects’ safety and/or compliance with trial procedures.
3. Life expectancy less than 6 months.
4. Subject has any currently active AIDS defining illness with the following exception:
- Stable, cutaneous Kaposi Sarcoma that is 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 compliance to adhere to the trial protocol procedures.
5. 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.
6. Subject has known or suspected acute (primary) HIV-1 infection.
7. Any use of NNRTIs.
8. Acute hepatitis A, B, or C infection.
9. Having documented genotypic evidence of NNRTI resistance at screening or from historical data available in the source documents.
A098G
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
10. Any current or history of adrenal disorder.
11. Receipt of any investigational drug within 90 days prior to the trial drug administration.
12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the
components of the investigational medication.
13. Pregnant or breastfeeding female.
14. 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 until 14 days after the end of the trial (or after last intake of ARVs).
Note: Hormonal based contraception may not be reliable when taking TMC278, therefore to be eligible for this trial, women of childbearing potential should either:
1) use a double barrier method to prevent pregnancy;
OR
2) use hormonal based contraceptive in combination with a barrier contraceptive;
OR
3) use an intrauterine device in combination with a barrier contraceptive;
OR
4) be non-heterosexually active, practice sexual abstinence or have a vasectomized partner.
Note: Women who are postmenopausal for at least 2 years, women with total
hysterectomy and women who have had a tubal ligation are considered of nonchildbearing potential.
15. Heterosexually active males without the use of 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 ARVs). All HIV-infected male subjects are advised to use a condom to reduce the risk of transmitting HIV. Since the effects of TMC278 on conception are unknown, non-vasectomized heterosexual male subjects are advised to use one of the following birth control methods:
- a condom with spermicide, or
- a condom or a spermicide combined with either hormonal contraceptives, IUD,
diaphragm, cervical cap or female condom, or
- refrain from heterosexual intercourse
from screening onwards until one month after the last study drug administration i.e., until the 30-days follow-up visit or one month after discontinuation of the study medication in case of premature discontinuation.
The use of the above mentioned birth control methods does not apply if the male HIVinfected subject has been vasectomized minimally one month prior to screening or if the female sexual partner has had a tubal ligation or a hysterectomy or if she is post-menopausal for at least 2 years.
For more details on the existing data in regards to the reproductive toxicity of TMC278,
please refer to the current IB.
16. Any of the abnormal laboratory values listed below:
- Renal impairment: serum creatinine > 2 x Upper Limit of Normal
- Hemoglobin toxicity grade 2 or greater according to the Division of AIDS
grading scale (d 8.4 g/dL)
- Platelet count < 75 x 109 cells/L (75000/mcL).
- Absolute neutrophil count < 1.0 x 109 cells/L (1000 cells/mcL).
- ALT or AST > 3 x ULN.
- Any grade 3 or 4 toxicity according to the DAIDS grading scale.
17. Subject with clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels ([INR] > 1.5 or albumin < 30 g/L or bilirubin ≥ 2.5 x ULN).
18. Chronic hepatitis B or C unless AST and ALT are < 3 x ULN, subject is clinically stable and does not meet the definition of decompensated liver function as in exclusion criteria 17, and AST and ALT have been stable over the 3 months prior to screening and platelets are within laboratory normal range.
19. Subjects with a CD4 cell count of < 100 cells/mm3
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy parameter is the proportion of subjects with undetectable viral load values (< 50 copies/mL) after 48 weeks of treatment (responders).
The potential effect of switching to TMC278 25 mg q.d. will be evaluated. |
|
| 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 | Yes |
| 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 |
|
| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| until w96: part. blinded:contr group open label+ TMC278 groups double blinded. After w96: open label |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 | 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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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