| 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 | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020192 |
| E.1.2 | Term | HIV-1 |
|
| 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 |
| •to evaluate the pharmacokinetic interaction between ETR and ATV/rtv at 2 different doses |
|
| E.2.2 | Secondary objectives of the trial |
•to assess the impact of cytochrome P450 (CYP) 2C9 and 2C19 genotypes on ETR
pharmacokinetics;
• to evaluate safety and tolerability of ETR in combination with ATV/rtv and 1 NRTI over
48 weeks;
• to evaluate the antiviral activity of ETR in combination with ATV/rtv and 1 NRTI over
48 Weeks;
• to evaluate the immunologic changes (as measured by CD4 cells) with ETR and ATV/rtv
with 1 NRTI over 48 weeks;
• to evaluate changes in viral genotype and drug susceptibility over 48 weeks. |
|
| 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 |
The substudy is included in the protocol final version dated 10 March 2009.
The objectives of the substudy are:
• to evaluate the pharmacokinetics of ETR, ATV, and ritonavir with and without coadministrtation of TDF;
• to evaluate short-term safety and tolerability of ETR + ATV/rtv + 1 investigator-selected NRTI + TDF. |
|
| E.3 | Principal inclusion criteria |
1. Male or female subjects, aged 18 years or above.
2. Subject has signed the informed consent form (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 500 HIV-1 RNA copies/mL.
6. Subject has received at least one HAART regimen
Note: HAART is defined as potent anti-HIV treatment usually including a combination
of 3 or more drugs with activity against HIV whose purpose is to reduce viral load to
undetectable. This regimen usually includes treatment with at least 2 NRTIs in
combination with at least 1 additional ARV from the NNRTI and/or PI class.
Note: Subjects on a structured treatment interruption for a minimum of 4 weeks at the time of screening are allowed.
7. On a stable antiretroviral therapy (ART) for at least 8 weeks at Screening and willing to stay on that treatment until the start of the Pre-Treatment Phase.
8. Presence of at least 1 of the following mutations (based upon the following list of
47 NNRTI RAMs: V90I, A98G, L100I, K101E/H/P/Q, K103H/N/S/T, V106A/I/M,
V108I, E138A/G/K/Q, V179D/E/F/G/I/T, Y181C/I/V, Y188C/H/L, V189I,
G190A/C/E/Q/S, H221Y, P225H, F227C/L, M230I/L, P236L, K238N/T, Y318F) on the
resistance test at Screening or from prior genotypic analysis, evidence of which should be available in the source documents and enrollment of the subject based on these data needs to be agreed upon by the sponsor.
9. Demonstrated sensitivity to ATV, ETR and at least one of the selected NRTIs based on the resistance test at Screening.
10.General medical condition, in the investigator’s opinion, does not interfere with the assessments and completion of the trial.
Subjects who meet all of the criteria above and the following criteria are eligible for the
substudy:
1. Currently enrolled in trial TMC125-C238 for > 24 weeks.
2. Informed Consent Form (ICF) signed voluntarily.
3. HIV-1 plasma viral load < 50 copies/mL on at least the 2 most recent consecutive visits.
4. General medical condition, in the investigator’s opinion, does not interfere with the
assessments and completion of the substudy. |
|
| E.4 | Principal exclusion criteria |
1. Primary HIV-1 infection.
2. Previously documented HIV-2 infection.
3. Previously failed 2 or more HIV PI-containing regimens.
4. Use of disallowed concomitant therapy.
5. Previous diagnosis of hereditary hyperbilirubinemia (eg. Gilbert’s syndrome, Crigler- Najjar syndrome).
6. 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.
7. Life expectancy less than 6 months according to the judgment of the investigator.
8. Subject has any currently active AIDS defining illness with the following exceptions, which must be discussed with the sponsor prior to enrollment:
a. Stable cutaneous Kaposi’s Sarcoma (i.e., no pulmonary or gastrointestinal
involvement other than oral lesions) that is unlikely to require any form of
systemic therapy during the trial period.
b. Wasting syndrome due to HIV infection if, in the investigator’s opinion, it is not
actively progressive and its treatment does not require hospitalization or
compromise the subject’s safety or compliance to adhere to trial related
procedures.
Note: An AIDS defining illness not clinically stabilized for at least 30 days will be
considered clinically active. Primary and secondary prophylaxis for an AIDS defining
illness is allowed in case the medication used is not part of the disallowed medication.
9. Any active clinically significant disease (e.g., pancreatitis, cardiac dysfunction) or
findings during screening of medical history, laboratory or physical examination that, in the investigator’s opinion, would compromise the subject’s safety or outcome of the trial.
10. Acute viral hepatitis including but not limited to A, B, or C.
11. Chronic hepatitis B and/or C co-infection.
12. Receipt of an investigational drug or investigational vaccine within 30 days prior to the trial drug administration.
13. Previously demonstrated clinically significant allergy or hypersensitivity to ETR or to any of the excipients of ETR.
14. Pregnant or breastfeeding female subject.
15. 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 medication;
Note: Hormone-based contraception may not be reliable when taking ARV agents;
therefore, to be eligible for this trial, women of childbearing potential should either:
• use a double barrier method to prevent pregnancy (i.e., using a male condom with
diaphragm or cervical cap); or
• use an hormonal contraceptive in combination with a barrier contraceptive (i.e.,
female/male condom, diaphragm or cervical cap); or
• use an intrauterine device (IUD) in combination with a barrier contraceptive (i.e.,
female/male condom, diaphragm or cervical cap); or
• do not engage in heterosexual sex, or have a vasectomized partner with confirmed
sterility.
Note: Women who are postmenopausal for at least 2 years and women with surgical
sterilization, i.e., tubal ligation or total hysterectomy, are considered of non-childbearing
potential.
Note: Spermicides contain 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.
16. Non-vasectomized 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 medication.
17. Any grade 3 or 4 laboratory abnormalities in aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, lipase, hemoglobin or neutrophils.
Note: Retesting of abnormal screening values that lead to exclusion will be allowed only once using an unscheduled visit during the Screening Period (to reassess eligibility).
18. Subjects who previously received treatment with either ETR (TMC125), dapivirine
(TMC120), or rilpivirine (TMC278).
Subjects meeting one or more of the following criteria cannot be selected for the substudy:
1. Previously demonstrated clinically significant allergy or hypersensitivity to TDF or to any of the excipients of TDF.
2. Any grade 3 or 4 serum creatinine abnormalities or a calculated creatinine clearance (CLcr) < 50 mL/min. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The first analysis will be performed when all subject have been treated with ETR for 12 weeks or discontinued earlier. The purpose of this analysis is mainly to evaluate the pharmacokinetics, safety, and short-term antiviral responses.
|
|
| 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 | No |
| 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 | 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, antiviral activity, immunological changes, viral genotype 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) | 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 | No |
| 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 | 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 | 4 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
Print
