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Comparative Efficacy and Safety Study of Dolutegravir and Lopinavir/Ritonavir in Second-line Treatment

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified September 2014 by ViiV Healthcare
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT02227238
First received: August 25, 2014
Last updated: October 2, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: DTG
Drug: LPV/RTV
Drug: Two NRTIs
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    The proportion of responders (HIV-1 RNA <50 c/mL) among randomized subjects who receive at least one dose of study medication (ITT-E population) will be assessed at Week 48 according to the FDA's Snapshot algorithm. Non-responders are subjects with HIV-1 RNA >=50 c/mL, without HIV RNA data at Week 48, subjects with background ART substitutions not permitted per protocol and subjects with background ART substitutions permitted per protocol after Week 4 but where their last HIV-1 RNA result prior to the date of decision to switch was >=50 c/mL.


Secondary Outcome Measures:
  • Proportion of subjects with plasma HIV-1 RNA <50 c/mL using the Snapshot algorithm [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    The proportion of responders (HIV-1 RNA <50 c/mL) will be assessed at Week 24 according to the FDA's Snapshot algorithm. Non-responders are subjects with HIV-1 RNA >=50, without HIV RNA data at Week 24, subjects with background ART substitutions not permitted per protocol and subjects with background ART substitutions permitted per protocol after Week 4 but where their last HIV-1 RNA result prior to the date of decision to switch was >=50 c/mL.

  • Proportion of subjects with plasma HIV-1 RNA <400 c/mL using the Snapshot algorithm [ Time Frame: Week 24, Week 48 ] [ Designated as safety issue: No ]
    The proportion of responders (HIV-1 RNA <400 c/mL) will be assessed at Weeks 24 and 48 according to the FDA's Snapshot algorithm. Non-responders are subjects with HIV-1 RNA >=400, without HIV RNA data at Week 24/48, subjects with background ART substitutions not permitted per protocol and subjects with background ART substitutions permitted per protocol after Week 4 but where their last HIV-1 RNA result prior to the date of decision to switch was >=50 c/mL.

  • Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48 [ Time Frame: Week 24, Week 48 ] [ Designated as safety issue: No ]
    Failure will be defined as treatment-related discontinuation (meeting confirmed virologic withdrawal criteria, treatment-related adverse event, safety stopping criteria, and lack of efficacy)

  • Time to viral suppression [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
    Time to HIV-1 RNA <50 c/mL

  • 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 ] [ Designated as safety issue: No ]
    Blood samples will be collected for assessment of lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+ cell count counts)

  • Incidence of disease progression [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
    Antiviral and immunological activity evaluated by incidence of disease progression (HIV-associated conditions, Acquired immune deficiency syndrome and death) over time

  • Incidence and severity of Adverse Events (AEs) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
    AE is Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

  • Incidence and severity of laboratory abnormalities [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
    Laboratory parameters include haematology, clinical chemistry, and urinalysis.

  • Change from Baseline in fasting Low density lipoprotein (LDL)cholesterol [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
    Samples for lipid measurements will be obtained in a fasted state

  • Change from Baseline in fasting Total cholesterol / High density lipoprotein ratio [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
    Samples for lipid measurements will be obtained in a fasted state

  • Incidence of maximum post-Baseline emergent Grade 2 or greater laboratory abnormalities in fasting LDL cholesterol [ Time Frame: Week 24, Week 48 ] [ Designated as safety issue: No ]
    Samples for lipid measurements will be obtained in a fasted state

  • Incidence of maximum post-Baseline emergent Grade 2 or greater drug-related diarrhoea [ Time Frame: Week 24, Week 48 ] [ Designated as safety issue: No ]
    Grade 2, 3 or 4 diarrhoea (as per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events) considered by the investigator to be related or possibly related to study drug

  • Proportion of subjects who discontinue treatment due to AEs [ Time Frame: up to Week 52 ] [ Designated as safety issue: No ]
    Proportion of subjects who discontinue treatment due to AEs will be determined throughout the study

  • Change from Baseline, using the Gastrointestinal Symptom Rating Scale (GSRS) [ Time Frame: Week 4, Week 24, Week 48 ] [ Designated as safety issue: No ]
    GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhoea and Constipation. The GSRS will be administered as a paper questionnaire.

  • Change from Baseline in treatment satisfaction, using the HIV-Treatment Satisfaction Questionnaire (HIVTSQ) [ Time Frame: Week 4, Week 24, Week 48 ] [ Designated as safety issue: No ]
    HIVTSQ is self-reported scale that measure overall satisfaction with treatment and by specific domains, e.g. convenience, flexibility. The HIVTSQ will be administered as a paper questionnaire.

  • 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 ] [ Designated as safety issue: No ]
    It is self-reported scale with eight-items. Scores of 8 indicate high or near perfect adherence, and scores of 6 or less indicate poor or inadequate adherence on the MMAS-8 scale.

  • 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 ] [ Designated as safety issue: No ]
    Viral genotype and phenotype for both Baseline samples and from samples collected at the time of meeting a virologic withdrawal criterion may be analysed


Estimated Enrollment: 612
Study Start Date: October 2014
Estimated Study Completion Date: August 2018
Estimated Primary Completion Date: August 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DTG arm
Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator
Drug: DTG
DTG is supplied as 50 mg tablets
Drug: 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: LPV/RTV arm
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
Drug: LPV/RTV
LPV/RTV is supplied as the LPV/RTV oral tablet, which contains 200 mg of LPV and 50 mg of RTV
Drug: 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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02227238

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Sponsors and Collaborators
ViiV Healthcare
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare
  More Information

No publications provided

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT02227238     History of Changes
Other Study ID Numbers: 200304
Study First Received: August 25, 2014
Last Updated: October 2, 2014
Health Authority: Colombia: INVIMA
China: CFDA
Kenya: PPB
Brazil: National Health Surveillance Agency
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
South Africa: MCC
Chile: ISP
Thailand: FDA
Romania: National Medicines Agency
Mexico: COFEPRIS
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs

Keywords provided by ViiV Healthcare:
integrase inhibitor
second-line treatment
dolutegravir
HIV-1
antiretroviral therapy-experienced
non-inferiority
lopinavir/ritonavir

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Immune System Diseases
Lentivirus Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Dolutegravir
Lopinavir
Reverse Transcriptase Inhibitors
Ritonavir
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
HIV Integrase Inhibitors
HIV Protease Inhibitors
Integrase Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Protease Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014