| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HIV-1 infected, integrase inhibitor-naïve, therapy-experienced adult subjects |
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| E.1.1.1 | Medical condition in easily understood language |
| HIV-1 infection in adults who have never taken Integrase Inhibitor HIV medication previously but have taken Antiretroviral therapy before |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008922 |
| E.1.2 | Term | Chronic infection with HIV |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 demonstrate the antiviral efficacy of GSK1349572 50 mg once daily compared to RAL 400 mg BID both in combination with a background regimen consisting of one to two (1-2) fully active single agents in HIV-1 infected, integrase inhibitor-naïve, therapy-experienced subjects at 48 weeks. |
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| E.2.2 | Secondary objectives of the trial |
•To demonstrate antiviral efficacy of GSK1349572 50 mg once daily compared to RAL 400 mg BID both in combination with a background regimen consisting of one to two fully active single agents in HIV-1 infected, integrase inhibitor-naïve, therapy-experienced subjects at 24 weeks.
•To compare the tolerability, long-term safety, antiviral efficacy, and immunologic activity of GSK1349572 50 mg once daily to RAL 400 mg BID, both in combination with a background regimen, over time.
•To assess the development of viral resistance in subjects experiencing virological failure.
•To characterize the PK of GSK1349572 using sparse PK sampling strategy and population-modeling approach.
•To explore exposure-response relationships (e.g., the relationship between GSK1349572 plasma exposure and virologic response or occurrence of AEs) over time.
For remaining secondary objectives please see: page 21 of Protocol. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ART-experienced, HIV-1 infected subjects >18 years of age.
2.A female subject is eligible to enter and participate in the study if she:
a.is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and >45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or,
b.is of child-bearing potential, with a negative pregnancy test at both Screen and Day 1 and agrees to one of the following methods of contraception to avoid pregnancy:
•Complete abstinence from intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all study medications.
•Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide).
•Approved hormonal contraception may be administered with GSK1349572 (see the SPM for a listing of examples of approved hormonal contraception).
•Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion, see the SPM for an example listing of approved IUDs).
•Any other method with published data showing that the expected failure rate is <1% per year.
Any contraception method must be used consistently and in accordance with the approved product label.
All subjects participating in the study should be counseled on safer sexual practices including the use of effective barrier methods (e.g. male condom/spermicide).
3.HIV-1 infection as documented by HIV-1 RNA >400 c/mL at Screening and with at least one consecutive HIV-1 RNA >400 c/mL within the four months prior to Screening (unless the Screening HIV-1 RNA is > 1000 c/mL where no additional plasma HIV-1 RNA assessment is needed). (If an additional HIV-1 RNA within four months prior to Screening is not available, a second HIV-1 RNA must be performed during the Screening period [after the first result is available] to serve as a confirmatory sample.)
4. Has documented resistance (via Screening resistance test) to two or more different classes of antiretroviral agents; genotypic resistance is defined by current [IAS, 2009] primary mutations and Monogram genotypic results; phenotypic resistance is defined as values greater than lower cut off for agents where available and by a clinical/biological cut off if an upper cut off is not available; entry resistance is defined by an assay which identifies any CXCR4-utilizing virus, e.g. Trofile; T20 resistance is defined as IC50 > susceptibility cutoff in PhenoSense entry assay. If Screening resistance results provide a fully active agent and do not show two class resistance, then historical resistance results from the subject’s most recent resistance testing may be used for subjects off ART for at least 1 month, after consultation with the study virologist and/or medical monitor.
• Historic genotypic resistance will be based on IAS Dec 2009 primary mutations guidance or Monogram genotypic results;
• Historic phenotypic resistance will be accepted only in the absence of corresponding genotypic resistance data, and will be determined based on cutoff criteria from specified platforms as detailed in the SPM;
• Resistance data must be from within 4 years prior to Study initiation unless it is from a platform listed in the SPM;
Further historic resistance guidance will be provided in the SPM. Historical resistance tests along with current Screening resistance tests, as available, should be used to aid in selection of background therapy. Note: retests of Screening genotypes/phenotypes/tropism assays are not allowed.
5. Is INI-naïve, defined as no prior exposure to any INI (e.g. RAL, elvitegravir, or GSK1349572).
6.Signed and dated written informed consent is obtained from the subject or the subject’s legal representative prior to screening.
7.For subjects enrolled in France: a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
Exclusionary medical conditions
1.Screening resistance test result indicates no fully active antiviral agents are available for design of the background regimen. For RT and PRO inhibition, fully active is defined by full phenotypic susceptibility (fold change [FC] in 50% inhibitory concentration (IC50) < lower clinical cutoff). Clinical/biological cut off’s should be used to assess activity if upper and lower cut off’s are unavailable for an agent. Entry inhibitor activity is defined by the assay which identifies a viral population as fully CCR5-tropic (e.g., CXCR4-utilizing virus not detected); T20 activity is defined as IC50 < susceptibility cut off in PhenoSense Entry assay.
2. Subject-virus does not yield results using genotype/phenotype/tropism at Screening (assay data is essential for eligibility determination.
3.Women who are breastfeeding.
4.Any evidence of an active Center for Disease and Prevention Control (CDC) Category C disease [CDC, 1993], except cutaneous Kaposi’s sarcoma not requiring systemic therapy or historic or current CD4+ cell count <200 cells/mm3 are not exclusionary.
5.Subjects with moderate to severe hepatic impairment as defined by Child-Pugh classification (see Appendix 11.1).
6.Recent history (<3 months) of upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding.
7.Anticipated need for HCV therapy during the study.
8.History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
9.History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma; other localized malignancies require agreement between the investigator and study medical monitor for inclusion of the subject.
Exclusionary Treatments prior to Screening or Day 1
10.Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to Screening.
11.Treatment with any of the following agents within 28 days of Screening:
•radiation therapy,
•cytotoxic chemotherapeutic agents,
•any immunomodulator.
12.Treatment with any agent, other than licensed ART, which has documented activity against HIV-1 in vitro within 28 days of first dose of IP administration.
13.Exposure to an experimental drug and/or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the experimental test agent - whichever is longer, prior to the first dose of IP.
14.French subjects recruited at sites in France will be excluded if the subject has participated in any study using an investigational drug and/or vaccine 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 or the subject plans to participate simultaneously in another clinical study.
Exclusionary Lab Values or Clinical Assessments at Screening
15.Any verified Grade 4 laboratory abnormality (a single repeat test is allowed during the Screening period to verify a Grade 4 result). Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the subject’s participation in the study of an investigational compound is exclusionary.
16.Alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN).
17.ALT > 3xULN and bilirubin > 1.5xULN (with >35% direct bilirubin).
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for this study is the proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using a Missing, Switch, or Discontinuation = Failure (MSDF) algorithm as codified by the FDA’s “snapshot” algorithm (see Section 8.3.2 of Protocol). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• The proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the MSDF algorithm.
• The proportion of subjects with detectable virus that has genotypic or phenotypic evidence of INI resistance by Week 48 (or Week 24).
• Proportion of subjects with plasma HIV-1 RNA <400 c/mL and <50 c/mL at Week 24.
• Proportion of subjects with plasma HIV-1 RNA <400 c/mL at Week 48.
• Absolute values and changes from baseline in CD4+ and CD8+ cell counts over time.
• Incidence of disease progression (HIV-associated conditions, AIDS and death).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| 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) | 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 | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.1.7.1 | Other trial design description |
| 48 week double blind randomised phase followed by open label phase for subjects receiving GSK1349572 |
|
| 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.8.2.3.1 | Comparator description |
|
| 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.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 | 3 |
| 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 | 3 |
| 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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