A Pilot Study Assessing the Integrase Inhibitor GSK1349572 in HIV-infected Persons With Virus Resistant to Raltegravir

A Pilot Study to Assess the Antiviral Activity of GSK1349572 Containing Regimen in Antiretroviral Therapy (ART)-Experienced, HIV-1-infected Adult Subjects With Raltegravir Resistance

Integrase is an enzyme produced by HIV so that the virus can multiply in the human body. GSK1349572 is a new drug in the integrase inhibitor class that prevents the enzyme from working properly and therefore prevents the virus from multiplying.

GSK1349572 has shown to be effective against viruses in a short-term monotherapy study in adults with no previous exposure to integrase inhibitors. The purpose of this study is to determine whether GSK1349572 is effective in the treatment of HIV-infected patients who no longer respond to treatment with the approved integrase inhibitor raltegravir and carry viruses with resistance to this drug. The safety and efficacy of GSK1349572 50mg once daily in combination with the background HIV drugs previously administered (unless discontinuation of a particular drug is required) will be assessed over 10 days (functional monotherapy phase), followed by the evaluation of the safety and efficacy of GSK1349572 given with a new optimised background regimen from Day 11 through at least Week 24.

Study (ING112961) is a Phase IIb, multicentre, open-label, single arm, two cohorts, pilot study to assess the antiviral activity of GSK1349572 containing regimen in HIV-1 infected ART-experienced adults with raltegravir (RAL) resistance. The study will include approximately 50 ART-experienced subjects with either current or past virologic failure to RAL. All subjects must harbour isolates with RAL resistance mutations at Screening. Subjects should also have documented genotypic and/or phenotypic resistance to at least one compound from each of three or more of the approved classes of ART (including integrase inhibitors [INIs]). Subjects with current RAL virologic failure will substitute RAL with GSK1349572 50mg once daily and continue the remaining components of their failing regimen through Day 10. Subjects with historical RAL virologic failure will add GSK1349572 50mg once daily to their failing regimen through Day 10. On Day 11 all subjects will continue GSK1349572 and optimize their background therapy. Antiviral activity, safety and tolerability of GSK1349572 will be evaluated at Day 11 and over time through at least Week 24.

ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship.

Inclusion Criteria:

• HIV-1 infected male or female adults at least 18 years of age with a plasma HIV-1 RNA > 1,000 copies/mL at study entry. Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol)
• ART-experienced (defined as on stable ART for at least the last 2 months) and is either currently experiencing virologic failure to RAL or experienced virologic failure to RAL > 8 weeks prior to Screening
• Must have documented RAL genotypic resistance on study entry genotype
• Must have documented genotypic or phenotypic resistance to at least one drug from each of three or more of all approved classes of ART
• For Cohort II, Subjects MUST be able to receive at least one fully active drug as part of the Day 11 optimised background regimen
• Willing and able to understand and provide signed and dated written informed consent prior to screening

Exclusion Criteria:

• Any pre-existing mental, physical, or substance abuse disorder which, which could compromise ability to comply with the protocol or compromise subject safety
• Women who are pregnant or breastfeeding
• An active AIDS-defining condition at the screening visit
• Currently take and/or anticipated need for EFV, NVP, FPV/RTV or TPV/RTV during the study
• Treatment with any of the following medications within 15 days of starting study drug, or anticipated to need, during the course of the study: Etravirine (unless co-administered with LPV/RTV or DRV/RTV), rifampin, rifabutin, phenytoin, phenobarbital, barbiturates, glucocorticoids, modafinil, oxcarbazepine, pioglitazone, troglitazone, carbamazepine, St. Johns wort
• Previous participation in an experimental drug and/or vaccine trial(s) within 30 days or 5 half-lives
• History of ongoing or clinically relevant pancreatitis or hepatitis within the previous 6 months
• Expected to require treatment for HCV infection during the first 24 weeks of the study
• Evidence of cirrhosis with or without hepatitis viral co-infection
• History of upper gastrointestinal bleed and/or active peptic ulcer disease
• Screening haemoglobin <10g/dL (100g/L)
• Subject suffers from a serious medical condition which could compromise the safety of the subject.
• Any condition that could interfere with the absorption, distribution, metabolism or excretion of the drug or render the subject unable to take oral medication
• Screening lipase 3 times the upper limit of normal (ULN)
• Any acute or Grade 4 laboratory abnormality at screening
• Screening alanine aminotransferase (ALT) >5xULN
• Screening ALT 3xULN and bilirubin 1.5xULN (with 35% direct bilirubin)
• Personal or family history of prolonged QT syndrome.
• Any clinically significant finding, as specified in the protocol, on screening or baseline electrocardiograph (ECG)
• History of allergy to the study drugs or their components or drugs of their class
• Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 28 days prior to screening, or future need of treatment with these agents during the study
• Treatment with immunomodulators within 28 days prior to screening or subject has received an HIV-1 vaccine within 90 days prior to screening