| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of HIV-1 infection. |
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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 |
To select the GW640385 (385) dose for further study from comparisons of the dosing regimens of 385/RTV twice daily (BID) plus continued nucleoside or nucleotide reverse transcriptase inhibitor (N[t]RTI) background therapy to maintenance of current single RTV-boosted PI containing regimens in PI-experienced adult subjects based on the:
• effect on virologic markers of HIV-1 infection
• 385 trough concentration (C τ) at Day 15
• short-term safety and tolerability of the 385/RTV BID containing regimens
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| E.2.2 | Secondary objectives of the trial |
• Assess the early antiviral and immunologic activity of the 385/RTV BID containing regimens
• Evaluate the long-term safety, antiviral activity and tolerability of the 385/RTV BID containing regimen(s)
• Explore Day 1 covariates (eg demographics, virology etc.) and pharmacokinetic factors that may be associated with antiviral activity and adverse events (AEs)
• Examine incidence of Day 1 genotypic and phenotypic cross-resistance to 385 in PI-experienced subjects and its impact on treatment response
• Assess on therapy and treatment emergent viral resistance patterns and compare these patterns with treatment outcome
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1.HIV-infected adult male aged ≥18 OR
HIV-infected adult female ≥18 if she is of:
a.non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchial); or,
b.child-bearing potential with a negative pregnancy test at screen, a negative pregnancy test on Day 1 and who agrees to use one of the methods of contraception listed below. Premenarchial females who develop child-bearing potential while on the study will be expected to follow one of the methods of contraception listed below.
•Agreement for complete abstinence from intercourse from 2 weeks prior to administration of study drugs, throughout the study and for 2 weeks after discontinuation of all study medications. Should a female subject of childbearing potential decide to become sexually active during the course of the study, she must be counseled and be willing to use one of the other contraception methods listed below:
•Double barrier contraception (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide)
•Any intrauterine device (IUD) with published data showing that the expected failure rate is less than 1% per year (not all IUDs meet this criterion)
•Any other method with published data showing that the lowest expected failure rate for that method is less than 1% per year.
Any contraception method must be used consistently and correctly, i.e., in accordance with both the product label and the instructions of a physician. Note: hormonal contraceptives are not considered a sufficient form of contraception for this study. All subjects of childbearing potential or developing child-bearing potential while participating in this study should be counseled on the practice of safe/safer sex.
2.Plasma HIV-1 RNA ≥1,000 copies/mL at Screening.
3.Evidence of at least two or more multi-PI resistance mutations (L10I/F/V/R, V32I, M46I/L, I54V/L/M, V82A/F/T/S, I84V/A/C, L90M) at Screening or within three months prior to Screening.
4.Subjects currently receiving a regimen that has not changed for at least 8 weeks prior to Screening and which contains a single RTV-boosted PI, excluding TPV/RTV (total daily dose of RTV must be ≤ 200mg)
•In the absence of historic genotypic data confirming eligibility, subject must also have received at least one other PI (with or without RTV) for at least 8 weeks (which may have included TPV/RTV)
5.Ability to understand and comply with protocol requirements, instructions and protocol-stated restrictions.
6.Subject is willing and able to understand and provide signed and dated written informed consent prior to participation in this study.
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Subject requiring a change in their current ART therapy between Screening and Day 1.
2. Current administration of an NNRTI, TPV or dual RTV- boosted PI as part of their ART regimen at Screening.
3. Active CDC HIV-1 Category C disease except cutaneous Kaposi’s Sarcoma not requiring systemic therapy at entry.
4. Pregnant women or women who are breastfeeding.
5. Current or history of thyroid abnormality which requires or has required treatment.
6. History of clinically relevant pancreatitis or hepatitis within the previous 6 months of investigational product administration.
7. Significant blood loss (1 pint of whole blood) within 56 days of the Screening visit.
8. Condition which might interfere with the absorption, distribution, metabolism or excretion of the drug e.g., diabetes mellitus, hyperthyroidism, malabsorption syndrome, chronic diarrhea (>3 stools/day).
9. Condition which may interfere with the subject’s ability to comply with the dosing schedule and protocol evaluations (including alcohol or drug abuse) or which might compromise the safety of the subject.
10. History of a drug or other allergy which contraindicates the subject’s participation in the study or known hypersensitivity to the investigational product(s) to be administered in this study
11. Any clinically significant finding on Screening or Day 1 ECG. Includes subjects with any repolarization delay (resting QTcB interval >450 msec at the Screening or Day 1 visit [mean of the three Day 1 values]). Subjects with a history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia) will also be excluded.
12. Acute laboratory abnormality at Screening which should preclude the subject’s participation in the study of an investigational compound.
13. Grade 4 laboratory abnormality at Screening with the exception of creatine phosphokinase (CPK). Subjects with an identifiable temporary cause for Grade 4 CPK (e.g. strenuous exercise) may, after consultation with GSK, have a repeat CPK assessment during the Screening period provided it occurs at least 7 days after the initial finding. If on repeat testing the CPK value is ≥ Grade 1, the subject may enter the study providing s/he meets all other eligibility requirements.
14. Grade 3 (5 -10 times upper limit of normal [ULN]) alanine aminotransferase or aspartate aminotransferase within 28 days of Day 1
15. Inadequate renal function at Screening, defined as:
•serum creatinine >1.5mg/dL
•calculated creatinine clearance (CrCl) ≤60 mL/min
16. Need for use of dual boosted PI, or an NNRTI as part of their background ART (all treatment arms) during the Randomized Phase OR the use of TMC-114 as the Control Arm C boosted-PI from Day 15 until the subject enters the Non-Randomized Phase of the study.
Note: Use of NNRTIs, dual RTV-boosted PIs and TMC-114 will be permitted during the Non-Randomized phase for Control Arm C subjects who have not switched to a 385 containing regimen. For subjects receiving a 385 containing dosing regimen, use of these agents would be dependent on the available drug-drug interaction data that has been communicated to the site.
17. Treatment with other investigational drugs/therapies within 60 days prior to Screening.
18. Subject has received an HIV-1 immunotherapeutic vaccine within 90 days prior to Screening.
19. Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 days of investigational product administration or anticipated need for such treatment within the study.
20. Treatment with immunomodulating agents (such as systemic or inhaled corticosteriods, interleukins, interferons) or any agent with known anti-HIV-1 activity but not approved for that indication (such as hydroxyurea, foscarnet) within 30 days of investigational product administration.
21. Subjects who cannot refrain from drinking grapefruit juice or eating grapefruit within:
• 3 days prior to the first dose of investigational product(s) – all subjects
• through Day 15 - all subjects receiving 385
22. Treatment with the following medications within 30 days of commencement of study drug or an anticipated need during the study (see list provided in protocol for details).
23. Subjects recruited at sites in France will be excluded if:
•The subject is not affiliated with or a beneficiary of a social security.
•The subject has previously participated in an experimental drug and/or vaccine trial(s) within 60 days or 5 half –lives, or twice the duration of the biological effect of the experimental drug or vaccine – whichever is longer, prior to screening for the study.
•The subject will participate simultaneously in another clinical study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Absolute change from Day 1 in plasma HIV-1 RNA over 15 days,
• Proportion of subjects with Day 15 385 C τ above target concentrations (28 ng/mL),
• Changes over time in laboratory parameters and the nature and frequency of clinical AEs through the last subject enrolled completing their Day 15 visit.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Viral resistance measurements (genotype/phenotype) |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Partially blinded; GW640385 dose blinded |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Continued therapy with protease inhibitor/ritonavir |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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