Study Assessing Dolutegravir in HIV-1 Infected Subjects With Virus Resistant to Raltegravir and/or Elivitegravir

A Phase III Randomized, Double-blind Study to Demonstrate the Antiviral Activity of Dolutegravir (DTG) 50 mg Twice Daily Versus Placebo Both Co-Administered With a Failing Antiretroviral Regimen Over Seven Days, Followed by an Open Label Phase With All Subjects Receiving DTG 50 mg Twice Daily Co-administered With an Optimised Background Regimen (OBR) in HIV-1 Infected, Integrase Inhibitor Therapy-Experienced and Resistant, Adults

Study ING116529 is a multicenter, randomized, study with an initial 7 day placebo- controlled, functional monotherapy phase to quantify the antiviral activity attributable to dolutegravir (DTG) in HIV-1 infected, ART-experienced adults who are experiencing virological failure on an Integrase inhibitor containing regimen (current RAL or ELV failures), with evidence of genotypic resistance to RAL or ELV at study entry. Thirty subjects will be randomized (1:1) to receive either DTG 50mg BID (Arm A) or Placebo (Arm B) with the current failing regimen for 7 days (RAL or ELV should be discontinued prior to dosing with DTG). At Day 8, subjects from both arms will enter an open label phase and receive open label DTG 50mg BID with an optimized background regimen containing at least one fully active drug.

Study ING116529 is a multicenter, randomized, study with an initial 7 day placebo-controlled, functional monotherapy phase to assess the antiviral activity and safety of a dolutegravir (DTG, GSK1349572) containing regimen in HIV-1 infected, ART-experienced adults with virological failure on an integrase inhibitor (INI) containing regimen.

Subjects must have evidence of genotypic resistance to raltegravir [RAL] or elvitegravir [ELV] at Screening and documented current or historical genotypic or phenotypic resistance to at least two other antiretroviral therapy drug classes.

The study is designed to provide an accurate measure of the intrinsic antiviral activity of DTG 50mg twice daily versus placebo both administered with the current failing regimen in a randomised double-blind phase to Day 8. This will be followed by an open label phase with all subjects receiving DTG 50mg twice daily with an optimized background regimen (containing at least one fully active drug) until subjects no longer derive clinical benefit or until DTG is locally available. Thirty subjects will be randomized (1:1) to receive either DTG 50mg BID (Arm A) or Placebo (Arm B) with the current failing regimen for 7 days (RAL or ELV should be discontinued prior to dosing at Day 1). At Day 8, subjects from both arms will enter an open label phase and receive open label DTG 50mg BID with an optimized background regimen containing at least one fully active drug The primary analysis will be conducted after the last subject enrolled has completed the randomised, double-blind phase at Day 8. Additional analyses may be performed prior to study closure when all ongoing subjects transition to locally available commercial DTG.

Inclusion Criteria:

• Screening plasma HIV-1 RNA ≥1000 copies/mL
• ART-experienced, INI-experienced, DTG naïve
• Current virological failure on raltegravir (RAL) or elvitegravir (ELV) regimen
• The subject's HIV-1 shows genotypic resistance to RAL or ELV at Screening
• Subject has been on stable ART for at least one month prior to Screening and through Day 1(with exceptions for ETV, EFV and NVP that can be interrupted within 14 days of Day 1, see Exclusion Criterion)
• Documented resistance to at least one drug from each of two or more of any approved classes of ART other than integrase inhibitors
• Be able to receive at least one fully active drug as part of the OBR from Day 8
• Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol)
• Willing and able to understand and provide signed and dated written informed consent prior to Screening.

Exclusion Criteria:

• Women who are pregnant or breast feeding
• An active AIDS-defining condition at Screening (except cutaneous Kaposi's sarcoma not requiring systemic therapy or CD4+ <200c/mm3)
• Moderate to severe hepatic impairment as defined by Child-Pugh classification
• Anticipated need for HCV therapy during the first 24 weeks of the study
• Recent history (less than or equal to 3 months) of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding
• Allergy or intolerance to the study drugs or their components or drugs of their class
• Malignancy within the past 6 months
• Treatment with an HIV-1 therapeutic vaccine within 90 days of Screening
• Treatment with radiation therapy, cytotoxic chemotherapeutic agents or any immunomodulator within 28 days of Screening
• Treatment with any agent, other than licensed ART, with documented in vitro/vivo activity against HIV-1 within 28 days of first dose of investigational product (with the exception of entecavir if required for Hep B treatment)
• Treatment with etravirine, efavirenz, or nevirapine within 14 days of Day 1(etravirine may be used if coadministered with lopinavir/ritonavir or darunavir/ritonavir)
• Treatment with tipranivir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir within 28 days prior to Screening
• Exposure to an experimental drug or vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, which ever is longer, prior to the first dose of IP.
• Any acute or verified Grade 4 laboratory abnormality (with the exception of Grade 4 lipids) at Screening
• ALT> 5 times the upper limit of normal (ULN) at Screening
• ALT ≥ 3X ULN and bilirubin > 1.5 X ULN (with 35% direct bilirubin) at Screening