HIV-1-infected adult subjects with treatment failure on an integrase inhibitor containing regimen MedDRA version: 14.1 Level: LLT Classification code 10008922 Term: Chronic infection with HIV System Organ Class: 10021881 - Infections and infestations
Conditions
Interventions
Product Name: dolutegravir
Product Code: GSK1349572
Pharmaceutical Form: Coated tablet
INN or Proposed INN: Dolutegravir
CAS Number: 1051375-19-9
Current Sponsor code: GSK1349572
Concentration unit:
Sponsors
Viiv Healthcare
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Subject has documented HIV-1 infection with a plasma HIV-1 RNA >=500 copies/mL at Screening. 2.Subject is ART-experienced and on stable ART for at least one month prior to Screening and through Day 1(with exceptions for ETV, EFV and NVP as detailed in Exclusion Criterion 11). 3.Subject is INI-experienced, but naïve to DTG, and either: •currently experiencing virologic failure to RAL or ELV or •experienced virologic failure while on therapy containing RAL or ELV (with documented genotypic and/or phenotypic INI resistance at time of failure) and is currently experiencing treatment failure on a subsequent regimen. 4.Subject harbours virus with : •Evidence of genotypic resistance to RAL and/or ELV on Screening resistance testing. •Evidence of phenotypic resistance to RAL on Screening resistance testing, OR •No evidence of resistance at Screening but documented historical genotypic and/or phenotypic resistance to RAL and/or ELV at time of prior INI virological failure, Phenotypic resistance is defined as the IC50 above the biological cut-off of the Phenosense assay for RAL (>1.5 FC versus wild type IC50). For ELV phenotypic resistance is defined as >2.5 FC above WT IC50. If assays other than the Monogram PhenoSense have been used to provide historical evidence of resistance, please discuss eligibility with the Study Virologist as specified in the Study Procedures Manual. 5.Subject harbours virus with documented genotypic or phenotypic resistance to at least one drug from each of two or more of all other approved classes of ART –N(t)RTIs, NNRTIs, PIs, fusion inhibitors, co-receptor inhibitors, based on Screening genotype/phenotype and/or historical genotype/phenotype data. 6.Subject must be able to receive at least one fully active drug in the OBR (to ensure an OSS ?1) from Day 8 onwards based on the subject’s Screening Monogram resistance test Net Assessment results. 7.Subject is >=18 years of age. 8.A female 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 use one of the methods of contraception listed below to avoid pregnancy: •Complete abstinence from intercourse from 2 weeks prior to administration of the investigational products, 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 DTG (see the SPM for a listing of examples of approved hormonal contraception, and Section 5.7.1), •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 lowest expected failure rate for that method is less than 1% per year. Any contraception method must be used consistently and in accordance with the approved product label and the instruction of a physician. The potential for drug interaction with background ARTs should also be considered (see Section 5.7.1) All subjects in t
Exclusion criteria
Exclusion criteria: Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. A single repeat test (re-test) per analyte is allowed during the screening period. Subjects meeting any of the following criteria must not be enrolled in the study: Exclusionary medical conditions 1.Women who are breastfeeding. 2.Any evidence of an active Center for Disease and Prevention Control (CDC) Category C disease [CDC, 1993; See Appendix 2]. This definition excludes cutaneous Kaposi’s sarcoma (KS) not requiring systemic therapy or current CD4+ cell levels <200cells/mm3 (i.e. subjects with cutaneous KS or <200 CD4+cells/mm3 are eligible for inclusion). 3.Subjects with moderate to severe hepatic impairment as determined by Child-Pugh classification (see Appendix 3). 4.Anticipated need for HCV therapy during the first 24 weeks of the study. 5.Recent history (<=3 months) of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding. 6.History or presence of allergy or intolerance to the study drugs or their components or drugs of their class. 7.History of malignancy within the past 6 months 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. Subjects with a history of anal intraepithelial neoplasia (AIN) or cervical intraepithelial neoplasia (CIN) may be included in the study. Exclusionary Treatments prior to Screening or Day 1 8.Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening. 9.Treatment with any of the following agents within 28 days of Screening: •radiation therapy, •cytotoxic chemotherapeutic agents, •any immunomodulator. 10.Treatment with any agent, other than licensed ART, with documented activity against HIV-1 in vitro within 28 days of first dose of IP. 11.Treatment with etravirine, efavirenz or nevirapine within 14 days of first dose of IP (etravirine only may be used if co-administered with LPV/RTV or DRV/RTV). 12.Treatment with tipranavir/ritonavir (TPV/RTV), fosamprenavir (FPV) or FPV/RTV within 28 days prior to Screening. 13.Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the 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 agent during the previous 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 will participate simultaneously in another clinical study. Exclusionary Lab Values or Clinical Assessments at Screening 15.Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol) abnormalities. A single repeat test is allowed during the Screening period to verify a result. 16.Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the subject’s
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To assess the antiviral activity of DTG 50mg twice daily (BID) administered failing background therapy to Day 8 and thereafter with with optimised background ART (OBR) consisting of at least one fully active agent through Week 24 in HIV-infected adult subjects with virological failure on a prior INI containing regimen. • To evaluate the safety and tolerability of DTG 50mg BID with background ART over time;Secondary Objective: • To assess the antiviral and immunologic activity of DTG over time • To assess the impact of different baseline INI genotypic resistant patterns and phenotype on treatment response (short and long term) to DTG • To characterise treatment emergent viral resistance in subjects experiencing virological failure • To characterise the pharmacokinetics (PK) of using a sparse PK sampling strategy and a population modeling approach • To evaluate the effect of patient characteristics (eg demographic factors) and concurrent medications (as covariates) on PK parameters of DTG • To explore, using multivariate models, the impact of Day 1 covariates (e.g. demographics, HIV RNA, resistance to DTG, overall susceptibility score of background ART) and PK on treatment response (e.g. antiviral activity, development of resistance, and/or AEs);Primary end point(s): The primary efficacy endpoint for hypothesis testing in this study will be the mean change from baseline in plasma HIV-1 RNA (log10 copies/mL) at Day 8, using a last observation carried forward (discontinuation equals baseline) (LOCFDB) dataset. The study’s primary objective is the characterisation of antiviral activity at both Day 8 and Week 24. The primary endpoint for assessment of Week 24 response will be the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 24 using a Missing, Switch or Discontinuation = Failure (MSDF) algorithm as codified by the FDA’s “snapshot” algorithm (see Section 8.3.2). (Please review Protocol Section 6.3.2);Timepoint(s) of evaluation of t | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Proportion of subjects with plasma HIV-1 RNA <400 copies/mL and <50 copies/mL over time •Absolute values and change from baseline in plasma HIV-1 RNA over time •Absolute values and changes from baseline in CD4+ and CD8+ cell counts over time •Incidence of HIV-1 disease progression (AIDS and death) (Please review Protocol Section 6.3.3);Timepoint(s) of evaluation of this end point: overtime through Weeks 24 and 48 | — |
Countries
Belgium, Italy, Portugal, Spain
Contacts
Public ContactClinical Trials Helpdesk
GlaxoSmithKline Research and Development Ltd
Outcome results
None listed