A Study to Assess Dolutegravir in HIV-infected Subjects With Treatment Failure on an Integrase Inhibitor Containing Regimen. (VIKING-3)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Shionogi
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01328041
First received: March 31, 2011
Last updated: August 1, 2013
Last verified: June 2013
  Purpose

The purpose of this trial is to assess the antiviral activity and safety of a dolutegravir (DTG) containing regimen in HIV-1 infected, antiretroviral therapy (ART)-experienced adults with current or historical failure on an integrase inhibitor (INI) containing regimen. The study will assess DTG 50mg twice daily administered initially with the current failing ART regimen but then with an optimised background ART regimen (OBR) after Day 7. The first analyses will be conducted after the last subject enrolled has completed 24 weeks. Subjects may remain on study after Week 24.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: dolutegravir
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Study to Demonstrate the Antiviral Activity and Safety of Dolutegravir in HIV-1 Infected Adult Subjects With Treatment Failure on an Integrase Inhibitor Containing Regimen.

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Mean change from Baseline in Plasma HIV-1 RNA at Day 8 [ Time Frame: Baseline and Day 8 ] [ Designated as safety issue: No ]
    Mean change from Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 8 was calculated as the Day 8 value minus the Baseline value. The last observation was carried forward if a participant had missed the Day 8 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 8. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 8.

  • Number of participants with HIV-1 RNA less than 50 copies/mL at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    The number of participants who had viral load <50 copies/mL at Week 24 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.

  • Number of participants with any Adverse Event (AE) or any serious adverse event (SAE) [ Time Frame: From the day of the first dose of study drug until study medication discontinuation or Week 24 analysis data cut-off (median of 169 study days) ] [ Designated as safety issue: No ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

  • Number of participants with Adverse Events of the indicated severity, per the Division of Acquired Immune Deficiency Syndrome (DAIDS) grading scale [ Time Frame: From the day of the first dose of study drug until study medication discontinuation or Week 24 analysis data cut-off (median of 169 study days) ] [ Designated as safety issue: No ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. AE/SAE severity was graded according to the DAIDS grading scale. The DAIDS displays events as Grades 1-4 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, potentially life threatening.

  • Number of participants with the maximum post-Baseline-emergent clinical chemistry toxicities of the indicated grade [ Time Frame: From the day of the first dose of study drug until study medication discontinuation or Week 24 analysis data cut-off (median of 169 study days) ] [ Designated as safety issue: No ]
    The severity of clinical chemistry toxicities was graded according to the DAIDS toxicity scale. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.

  • Number of participants with the maximum post-Baseline-emergent hematology toxicities of the indicated grade [ Time Frame: From the day of the first dose of study drug until study medication discontinuation or Week 24 analysis data cut-off (median of 169 study days) ] [ Designated as safety issue: No ]
    The severity of hematology toxicities was graded according to the DAIDS. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.


Secondary Outcome Measures:
  • Number of participants with plasma HIV-1 RNA less than 400 and 50 copies/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, and 24 [ Time Frame: Baseline; Day 8; and Weeks 4, 8, 12, 16, and 24 ] [ Designated as safety issue: No ]
    The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL was assessed at Baseline; Day 8; and Weeks 4, 8, 12, 16, and 24.

  • Mean change from Baseline in plasma HIV-1 RNA at Day 8 and Weeks 4, 8, 12, 16, and 24 [ Time Frame: Baseline; Day 8; Weeks 4, 8, 12, 16, and 24 ] [ Designated as safety issue: No ]
    Mean change from Baseline in plasma HIV-1 RNA was assesseed at Day 8 and Weeks 4, 8, 12, 16, and 24. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Absolute values for CD4+ and CD8+ cell counts at Weeks 4, 8, 12, 16, and 24 [ Time Frame: Weeks 4, 8, 12, 16, and 24 ] [ Designated as safety issue: No ]
    Absolute values for CD4+ and CD8+ cell counts were assessed at Weeks 4, 8, 12, 16, and 24.

  • Mean change from Baseline in CD4+ and CD8+ cell counts at Weeks 4, 8, 12, 16, and 24 [ Time Frame: Baseline and Weeks 4, 8, 12, 16, and 24 ] [ Designated as safety issue: No ]
    Mean change form Baseline in CD4+ and CD8+ cell counts was assessed at Weeks 4, 8, 12, 16, and 24. Change from Baseline was calculated as the post-Baselien value minus the Baseline value.

  • Ratio of CD4+/CD8+ cell count at Baseline and Weeks 4, 8, 12, 16, and 24 [ Time Frame: Baseline; Weeks 4, 8, 12, 16, and 24 ] [ Designated as safety issue: No ]
    The ratio of CD4+/CD8+ cell count was assessed at Baseline and at Weeks 4, 8, 12, 16, and 24. The ratio was calculated as the CD4+ cell count divided by CD8+ cell count.

  • Number of participants with HIV-1 disease progression (Acquired Immune Deficiency Syndrome [AIDS] or death) [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: No ]
    The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).

  • Cmax and Ctau of DTG [ Time Frame: Day 8, Week 4, and Week 24 ] [ Designated as safety issue: No ]
    The maximum plasma concentration (Cmax) and the concentration at the end of a dosing interval (Ctau) of DTG were assessed by a population pharmacokinetic (PK) modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.

  • AUC(0-tau) and AUC(0-24) of DTG [ Time Frame: Day 8, Week 4, and Week 24 ] [ Designated as safety issue: No ]
    The area under the time concentration curve over the dosing interval (AUC[0-tau]) and from 0 to 24 hours (AUC[0-24]) of DTG was assessed by a population PK modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.

  • C0 assessment of DTG [ Time Frame: Day 8, Week 4, and Week 24 ] [ Designated as safety issue: No ]
    The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 8, Week 4, and Week 24. Blood samples for pharmacokinetic assessments were collected pre-dose and 1-3 hours post-dose on Day 8 and at Week 4 and 4-12 hourspost-dose at Week 24. Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Parameter Population.

  • Number of participants with the indicated treatment-emergent integrase (IN) mutations detected at the time of protocol-defined virologic failure (PDVF) as a measure of genotypic resistance [ Time Frame: From the start of study treatment to date cut-off (median of 169 study days) ] [ Designated as safety issue: No ]
    An analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is a <0.5 log10 copies(c)/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 c/mL. PDVF after Day 8 is defined as virological non-respones (decrease in plasma HIV-1 RNA of <1 log10 c/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 c/mL and confirmed plasma HIV-1 RNA levels >=400 c/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 c/mL after prior confirmed suppression to <400 c/mL and confirmed plasma HIV-1 RNA levels >1 log10 c/mL above the nadir value [nadir: >=400 c/mL]).

  • Number of participants with the indicated fold increase in DTG FC (fold change in IC50 relative to wild-type virus) between Baseline and the time of PDVF, as a measure of post-Baseline phenotypic resistance [ Time Frame: From the start of study treatment to data cut-off (median of 169 study days) ] [ Designated as safety issue: No ]
    The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined as a <0.5 log10 copies/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 copies/mL. PDVF after Day 8 was defined for virological non-respones (decrease in plasma HIV-1 RNA of less than 1 log10 copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 copies/mL and confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL and confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL).


Enrollment: 175
Study Start Date: May 2011
Estimated Study Completion Date: January 2016
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: dolutegravir
dolutegravir plus background antiretroviral therapy optimised at Day 8
Drug: dolutegravir
50 mg twice daily

Detailed Description:

ING112574 is a Phase 3, multicentre, open-label, single arm study to assess the antiviral activity and safety of DTG containing regimen in HIV-1 infected ART-experienced adults with historical or current evidence of resistance to RAL or ELV. Initially, a minimum of 100 subjects will be enrolled to receive DTG 50mg twice daily with the current failing regimen for 7 days but with OBR from Day 8. Subjects must also have documented genotypic and/or phenotypic resistance to at least one compound in two or more of the other approved classes of ART but must also be able to include at least one fully active drug in the OBR to be started Day 8. The first data cut will take place after the (approximate) 100th subject enrolled completes the Week 24 visit. Enrollment will continue until a further 50 to 100 subjects have been recruited. All subjects who successfully complete 24 weeks of treatment will continue to have access to DTG until it is locally available as long as they continue to derive clinical benefit.

ViiV Healthcare is the sponsor of this study.

  Eligibility

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

Inclusion Criteria:

  • Screening plasma HIV-1 RNA ≥500 copies/mL
  • ART-experienced, INI-experienced, DTG naïve
  • Experienced virological failure on raltegravir (RAL) or elvitegravir (ELV) regimen
  • The subject's HIV-1 shows resistance to RAL or ELV at Screening or at prior time point of virological failure on RAL or ELV
  • Documented resistance to at least one drug from each of three or more of all approved classes of ART
  • 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 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 activity against HIV-1 in vitro within 28 days of first dose of investigational product
  • Treatment with etravirine, efavirenz, or nevirapine within 14 days of Day 1(etravirine may be used if coadministered with lopinivir/ritonavir or darunavir/ritonavir)
  • Treatment with tipranivir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir within 28 days prior to Screening
  • Verified Grade 4 laboratory abnormality 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01328041

  Show 65 Study Locations
Sponsors and Collaborators
ViiV Healthcare
Shionogi
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare
  More Information

No publications provided

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT01328041     History of Changes
Other Study ID Numbers: 112574
Study First Received: March 31, 2011
Last Updated: August 1, 2013
Health Authority: Italy: AIFA - Italian Ministry of Health
Spain: Agencia Española del Medicamento y Productos Sanitarios
Portugal: Infarmed - Autoridade Nacional do Medicamento e Produtos de Saúde, I.P.
Belgium: Agence Fédérale des Medicaments et des Produits de la Santé
United States: Food and Drug Administration
Canada: Health Canada
France: Agence Française de Sécurité Sanitaire des Produits de Santé

Keywords provided by ViiV Healthcare:
GSK1349572
resistance to raltegravir or elvitegravir
Integrase inhibitor
ART-experienced
dolutegravir

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immune System Diseases
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014