| 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 | 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 |
| MAIN PHASE To demonstrate non-inferiority in virologic response, defined as a confirmed plasma viral load of < 50 HIV-1 RNA copies/mL at Week 48 (as defined by the TLOVR algorithm), with DRV/rtv 800/100 mg q.d. versus DRV/rtv 600/100 mg b.i.d. in early ARV-experienced patients with a non-inferiority margin (delta) of 12%, when administered in combination with an individually selected OBR. EXTENSION PHASE AFTER WEEK 48 To provide DRV/rtv access as a 600/100 mg b.i.d. dosage via an extension phase of the TMC114-TiDP31-C229 trial to subjects who completed the 48 weeks of treatment with DRV/rtv in the main phase of the trial and continue to benefit from this treatment, and who live in a region where DRV is not yet commercially available, not yet reimbursed by the public and/or private health system or can not be accessed from another source (e.g., access program, government program). In addition, information on safety of DRV/rtv in combination with other ARVs will be monitored. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
- to evaluate safety and tolerabilityover 48 weeks;
- to evaluate the durability of efficacy over 48 weeks;
- to evaluate the change in viral load from baseline;
- to evaluate the percentage subjects with a confirmed plasma viral load < 400 HIV-1 RNA copies/mL;
- to evaluate the lipid effects of DRV/rtv q.d. versus b.i.d.;
- to compare the immunologic response;
- to evaluate resistance characteristics;
- to evaluate DRV and ritonavir pharmacokinetics following q.d. and b.i.d. dosing and explore the PK/PD relationship between: 1) DRV and efficacy/safety and 2) ritonavir and safety for b.i.d. and q.d. regimens;
- to determine and compare the subject-reported antiretroviral (ARV) medication adherence in subjects treated with DRV/rtv 800/100 mg q.d. versus DRV/rtv 600/100 b.i.d., both administered in combination with an individually selected OBR, at baseline and over 48 weeks. |
|
| 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 older.
2. Subjects with documented HIV-1 infection.
3. Stable HAART regimen for at least 12 weeks at screening.
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 PIs classes or a combination of 3 NRTIs.
4. In the investigator’s opinion, NNRTIs are not a valid treatment option, because of the subject’s ARV treatment history, ARV resistance testing, medication-taking behavior, safety and tolerance concerns, or other patient-related factors.
5. Prescreening or/and screening plasma HIV-1 RNA > 1,000 copies/mL (assayed by RNA PCR standard specimen procedure) on HAART regimen at screening.
Note: If no documented pre-screening viral load is available (taken at least 12 weeks after starting the HAART regimen the subject is on at screening and taken within 6 weeks before the screening visit), a pre-screening visit should be scheduled.
6. Screening genotype resistance test results showing none of the following mutations in the protease gene 11I, 32I, 33F, 47V, 50V, 54L, 54M, 74P, 76V, 84V and 89V, known as DRV resistance associated mutations [RAMs].
7. CD4+ cell count > 50 cells/µL.
8. Subjects have voluntarily signed the ICF.
9. Subjects can comply with the protocol requirements.
10. General medical condition, in the investigator’s opinion, does not interfere with the assessments and the completion of the trial. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting one or more of the following criteria cannot be selected.
1. Presence of any currently active conditions that fit the definition of the WHO clinical stage 4 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: Primary and secondary prophylaxis for an AIDS defining illness is allowed in case the medication used is not part of the disallowed medication.
2. Current or past alcohol and/or drug use which, in the investigator's opinion, could
compromise the subject's safety or adherence to the study protocol procedures.
3. Subjects for whom an investigational ARV is part of the current regimen, with the following exceptions if applicable (depending on local regulatory approval): tenofovir, emtricitabine.
Note: Participation in observational studies where no treatment is administered is allowed (if approved by sponsor). Upfront approval from the sponsor is needed in case additional blood is taken for other studies.
4. Previous or current use of ENF, tipranavir and/or DRV.
5. Use of disallowed concomitant therapy.
6. Life expectancy of less than 12 months.
7. Pregnant or breast-feeding.
8. 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: Estrogen hormonal based contraception may not be reliable when taking DRV/rtv, therefore to be eligible for this study, 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 non-estrogen 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 only non-heterosexually active, practice heterosexual abstinence, or have a vasectomized partner (confirmed sterile).
* a male and female condom should not be used together due to risk of
breakage or damage caused by latex friction.
Women who are postmenopausal for at least 2 years, and women with total
hysterectomy, and women with tubal ligation are considered of non-childbearing
potential.
9. Subjects with clinical or laboratory evidence of significantly decreased hepatic function or decompensation (i.e., liver insufficiency), irrespective of liver enzyme levels.
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 study 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 in case tenofovir and emtricitabine are included in the OBR.
10. Any active clinically significant disease (e.g., tuberculosis [TB], cardiac dysfunction,
pancreatitis, acute viral infections) or findings during screening of medical history or physical examination that, in the investigator’s opinion, would compromise the subjects safety or outcome of the trial.
11. Subjects with a grade 3 or 4 laboratory abnormality as defined by division of AIDS (DAIDS) grading tables, with the following exceptions unless clinical assessment foresees an immediate health risk to the subject:
- Subjects with asymptomatic triglyceride or cholesterol elevations of grade 3 or 4.
- Subjects with grade 3 or 4 bilirubin increases who use atazanavir as part of their
HAART regimen at screening.
12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication DRV or ritonavir.
Note: Darunavir 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 DRV has been identified in patients participating in phase II and Phase III trials.
13. Use of any non-ARV investigational agents within 60 days prior to screening without prior approval of the sponsor.
14. Participation in any other investigational trial without prior approval of the sponsor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Demonstration of non-inferiority in virologic response |
|
| 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 | 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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) | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| 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 | 11 |
| 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 | 11 |
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