Overview

This trial is active, not recruiting.

Condition infection, human immunodeficiency virus
Treatments dtg, lpv/rtv, two nrtis
Phase phase 3
Sponsor ViiV Healthcare
Collaborator GlaxoSmithKline
Start date December 2014
End date August 2017
Trial size 612 participants
Trial identifier NCT02227238, 200304

Summary

For treatment of human immunodeficiency virus type 1(HIV-1), publicly funded programmes tend to follow World Health Organization (WHO) guidelines to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs) for first-line antiretroviral therapy (ART); however, there is a need for further data on the best treatment options for people with HIV-1 who have virological failure with this first-line regimen. The number of patients failing on their first-line regimen is increasing thereby requiring a switch to second-line treatment to reduce accumulation of drug-resistance mutations, disease progression, HIV transmission, and death. WHO guidelines recommend second-line antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease inhibitor (PI); atazanavir (ATV) plus ritonavir (RTV) or lopinavir (LPV)/RTV are the preferred boosted PI options. This study is conducted to demonstrate non-inferior antiviral activity at 48 weeks of a dolutegravir (DTG) containing regimen compared to a WHO-recommended standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-1 infected patients failing first line therapy. This study comprises of a Screening Phase (approximately 28 to 42 days), a Randomized Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase. Approximately 612 subjects will be randomized 1:1 to receive DTG 50 milligram (mg) once daily or LPV/RTV (800/200 mg once daily or 400/100 mg twice daily, in accordance with investigator decision and local label), each added to an investigator selected background regimen of two NRTIs at least one of which needs to be fully active based on viral resistance testing at Screening. Subjects randomized to receive DTG who successfully complete 52 weeks of treatment will continue to have access to DTG until it is either locally approved and commercial supplies are available to patients or the patient no longer derives clinical benefit, or the patient meets a protocol-defined reason for discontinuation.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator
dtg
DTG is supplied as 50 mg tablets
two nrtis
Investigators will choose a dual NRTI background regimen for each subject . In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC
(Active Comparator)
Subjects will receive four oral tablets of200/50 mg LPV/RTV once daily or two oral tablets of 200/50 mg LPV/RTV twice daily plus two NRTIs selected by the investigator
lpv/rtv
LPV/RTV is supplied as the LPV/RTV oral tablet, which contains 200 mg of LPV and 50 mg of RTV
two nrtis
Investigators will choose a dual NRTI background regimen for each subject . In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC

Primary Outcomes

Measure
Proportion of subjects with plasma HIV-1 Ribonucleic acid (RNA) <50 copies/millilitre (c/mL) using the Snapshot algorithm (Missing, Switch or Discontinuation = Failure) for the ITT-E population
time frame: Week 48

Secondary Outcomes

Measure
Proportion of subjects with plasma HIV-1 RNA <50 c/mL using the Snapshot algorithm
time frame: Week 24
Proportion of subjects with plasma HIV-1 RNA <400 c/mL using the Snapshot algorithm
time frame: Week 24, Week 48
Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48
time frame: Week 24, Week 48
Time to viral suppression
time frame: Up to Week 48
Absolute values and changes from Baseline in cluster of differentiation 4 (CD4)+ cell counts at Weeks 24 and 48
time frame: Week 24, Week 48
Incidence of disease progression
time frame: Up to Week 48
Incidence and severity of Adverse Events (AEs)
time frame: Up to Week 52
Incidence and severity of laboratory abnormalities
time frame: Up to Week 52
Change from Baseline in fasting Low density lipoprotein (LDL)cholesterol
time frame: Baseline, Week 24, Week 48
Change from Baseline in fasting Total cholesterol / High density lipoprotein ratio
time frame: Baseline, Week 24, Week 48
Incidence of maximum post-Baseline emergent Grade 2 or greater laboratory abnormalities in fasting LDL cholesterol
time frame: Week 24, Week 48
Incidence of maximum post-Baseline emergent Grade 2 or greater drug-related diarrhoea
time frame: Week 24, Week 48
Proportion of subjects who discontinue treatment due to AEs
time frame: up to Week 52
Change from Baseline, using the Gastrointestinal Symptom Rating Scale (GSRS)
time frame: Week 4, Week 24, Week 48
Change from Baseline in treatment satisfaction, using the HIV-Treatment Satisfaction Questionnaire (HIVTSQ)
time frame: Week 4, Week 24, Week 48
Change from Baseline in adherence with treatment, using the Morisky Medication Adherence eight item scale (MMAS-8), at Weeks 4, 24 and 48
time frame: Week 4, Week 24, Week 48
Incidence of treatment-emergent genotypic and phenotypic resistance to DTG, LPV/RTV and other on-study ART in subjects meeting confirmed virologic withdrawal criteria
time frame: Up to Week 48

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - HIV-1 infected subjects >=18 years of age. - A female subject may be eligible to enter and participate in the study if she: 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, is of child-bearing potential, with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the protocol-defined methods of contraception to avoid pregnancy. - HIV-1 infection as documented by HIV-1 RNA >=400 c/mL at Screening. - Subject has been on a first-line treatment regimen consisting of an NNRTI plus two NRTIs for at least 6 months and is currently experiencing virologic failure to this first-line regimen defined as two consecutive (>=7 days apart) HIV-1 RNA results of >=400 c/mL. - Subjects must receive at least one fully active agent within the dual-NRTI background regimen for second line treatment. Fully active is defined by the Screening genotypic resistance report of the central laboratory (or a laboratory contracted by the central laboratory) showing no evidence of full or of partial resistance for a given NRTI which will be taken on study. - Subject is PI-naïve and Integrase inhibitor (INI)-naïve, defined as no prior or current exposure to any PI or INI. - Subject or the subject's legal representative is willing and able to understand and provide signed and dated written informed consent prior to screening. Exclusion Criteria: - Women who are breastfeeding. - Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic or current CD4+ cell levels <200 cells per cubic millimeter - Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification - Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). - Anticipated need for hepatitis C virus (HCV) therapy during the Randomised Phase of the study. - History or presence of allergy or intolerance to the study drugs or their components or drugs of their class. - Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localised malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject. - Subjects who in the investigator's judgment, poses a significant suicidality risk. Recent history of suicidal behaviour and/or suicidal ideation may be considered as evidence of serious suicide risk. - Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening. - Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, systemically administered immunomodulators. - Treatment with any agent, other than licensed ART as allowed above with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of IP. The exception is use of entecavir, in appropriate clinical situations, for treatment of hepatitis B [e.g. prior intolerance to Tenofovir (TDF), viral resistance to lamivudine (3TC) / Emtricitabine (FTC)] after discussion and agreement between the investigator and the medical monitor. - 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. - Any evidence of primary viral resistance to PIs or INIs based on the presence of any major resistance-associated mutation. - The subject's virus does not yield results using genotype at Screening (assay data is essential for eligibility determination). - Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 triglycerides. A single repeat test is allowed during the Screening period to verify a 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. - Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN) or ALT >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin)

Additional Information

Official title A Phase 3b, Randomized, Open-label Study of the Antiviral Activity and Safety of Dolutegravir Compared to Lopinavir/Ritonavir Both Administered With Dual Nucleoside Reverse Transcriptase Inhibitor Therapy in HIV-1 Infected Adult Subjects With Treatment Failure on First Line Therapy
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by ViiV Healthcare.