Study Assessing Dolutegravir in HIV-1 Infected Subjects With Virus Resistant to Raltegravir and/or Elivitegravir (VIKING-4)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Shionogi
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01568892
First received: March 29, 2012
Last updated: January 2, 2014
Last verified: December 2013
  Purpose

Study ING116529 is a multicenter, randomized, study with an initial 7 day placebo- controlled, functional monotherapy phase to quantify the antiviral activity attributable to dolutegravir (DTG) in HIV-1 infected, ART-experienced adults who are experiencing virological failure on an Integrase inhibitor containing regimen (current RAL or ELV failures), with evidence of genotypic resistance to RAL or ELV at study entry. Thirty subjects will be randomized (1:1) to receive either DTG 50mg BID (Arm A) or Placebo (Arm B) with the current failing regimen for 7 days (RAL or ELV should be discontinued prior to dosing with DTG). At Day 8, subjects from both arms will enter an open label phase and receive open label DTG 50mg BID with an optimized background regimen containing at least one fully active drug.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: dolutegravir 50 mg twice daily
Drug: dolutegravir placebo twice daily
Drug: Open-label dolutegravir 50mg twice daily
Phase 3

Access to an investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III Randomized, Double-blind Trial Investigating the Activity of Dolutegravir 50 mg BID vs Placebo Over 7 Days in HIV-1-infected Subjects With RAL/ELV Resistance, Followed by an Open-label Phase With an Optimized Background Regimen

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Mean Change From Baseline in Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) at Day 8 [ Time Frame: Baseline and Day 8 ] [ Designated as safety issue: No ]
    Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1) and Day 8. Change from Baseline was calculated as the value at Day 8 minus the value at Baseline (Day 1). The analysis was performed using statistical modeling correcting for Baseline plasma HIV-1 RNA, Baseline Dolutegravir (DTG) fold change (FC), the overall susceptibility score (OSS) of the failing regimen, and the interaction between DTG FC and treatment. Means and differences were calculated using the average Baseline DTG FC of the entire Intent-to-Treat Exposed (ITT-E) Population. The last observation carried forward with discontinuation equals Baseline (LOCFDB) dataset was used for the analysis. For the LOCFDB dataset, missing values were carried forward from the previous, non-missing, available on-treatment assessment, except formissing values due to premature withdrawal or Day 8 missing values, which had the Baseline value imputed.


Secondary Outcome Measures:
  • Absolute Values in Plasma HIV-1 RNA Over Time [ Time Frame: Baseline, Day 8, Day 28, and Week 8 ] [ Designated as safety issue: No ]
    Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1), Day 8, Day 28, Week 8, Week 12, Week 16, and Week 24. Too few participants reached post-Week 8 study visits, hence only data through Week 8 are presented.

  • Mean Change From Baseline in Plasma HIV-1 RNA Over Time [ Time Frame: Baseline, Day 8, Day 28, and Week 8 ] [ Designated as safety issue: No ]
    Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1), Day 8, Day 28, Week 8, Week 12, Week 16, and Week 24. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. Too few participants reached post-Week 8 study visits, hence only data through Week 8 are presented.

  • Number of Participants With Plasma HIV-1 RNA <50 c/mL Over Time [ Time Frame: Baseline, Day 8, Day 28, and Week 8 ] [ Designated as safety issue: No ]
    Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1), Day 8, Day 28, and Week 8, using the Food and Drug Administration's Snapshot algorithm. 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 Plasma HIV-1 RNA <400 c/mL Over Time [ Time Frame: Baseline, Day 8, Day 28, and Week 8 ] [ Designated as safety issue: No ]
    Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1), Day 8, Day 28, and Week 8, using the Food and Drug Administration's Snapshot algorithm. 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.

  • Absolute Values in Cluster of Differentiation 4+ (CD4+) Cell Counts Over Time [ Time Frame: Baseline, Day 8, Day 28, and Week 8 ] [ Designated as safety issue: No ]
    Blood samples were collected for lymphocyte subset assessment by flow cytometry at Baseline, Day 8, Day 28, and Week 8.

  • Median Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Counts Over Time [ Time Frame: Baseline, Day 8, Day 28, and Week 8 ] [ Designated as safety issue: No ]
    Blood samples were collected for lymphocyte subset assessment by flow cytometry at Baseline, Day 8, Day 28, and Week 8. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline.

  • Absolute Values in Cluster of Differentiation 8+ (CD8+) Cell Counts at Baseline and Day 28 [ Time Frame: Baseline and Day 28 ] [ Designated as safety issue: No ]
    Blood samples were collected for lymphocyte subset assessment by flow cytometry at Baseline and Day 28.

  • Median Change From Baseline in Cluster of Differentiation 8+ (CD8+) Cell Counts at Day 28 [ Time Frame: Baseline and Day 28 ] [ Designated as safety issue: No ]
    Blood samples were collected for lymphocyte subset assessment by flow cytometry at Baseline and Day 28. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline.

  • Number of Participants With the Indicated Type of HIV-1 Disease Progression (Acquired Immunodeficiency Syndrome [AIDS] or Death [DT]) [ Time Frame: From the day of the first dose of study drug until early withdrawal or the Day 8 analysis cut-off date (average of 14 study weeks) ] [ 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).

  • Number of Participants With Any Adverse Event (Serious and Non-serious) of the Indicated Grade [ Time Frame: From the first dose of study medication until early withdrawal or through the Day 8 analysis data cut-off date (average of 14 study weeks) ] [ Designated as safety issue: No ]
    An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (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; or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in other situations. Adverse events were graded for severity according to the Division of AIDS (DAIDS) toxicity scales as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening).

  • Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade [ Time Frame: From the first dose of study medication until early withdrawal or through the Day 8 analysis data cut-off date (average of 14 study weeks) ] [ Designated as safety issue: No ]
    Participants with post-Baseline-emergent clinical chemistry toxicities were analyzed. Clinical chemistry toxicities were graded for severity according to the Division of AIDS (DAIDS) toxicity scales as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening).

  • Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade [ Time Frame: From the first dose of study medication until early withdrawal or through the Day 8 analysis data cut-off date (average of 14 study weeks) ] [ Designated as safety issue: No ]
    Participants with post-Baseline-emergent hematology toxicities were analyzed. Hematology toxicities were graded for severity according to the Division of AIDS (DAIDS) toxicity scales as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening).

  • AUC(0-tau) of DTG [ Time Frame: Day 8, Day 28, and Week 24 ] [ Designated as safety issue: No ]
    The area under the time concentration curve over the dosing interval (AUC[0-tau]) of DTG was assessed using a population pharmacokinetic (PK) modeling approach. Blood samples for the determination of plasma DTG concentration were collected at the following time points: pre-dose and 1-3 hours (hrs) post-dose on Day 8; pre-dose and within a post-dose window (1-3 hours or 4-12 hours) on Day 28 and Week 24. For Day 8 PK, only samples collected from participants randomized to the active DTG arm were analyzed. Results from these PK parameters will be reported separately.

  • Cmax of DTG [ Time Frame: Day 8, Day 28, and Week 24 ] [ Designated as safety issue: No ]
    The maximal concentration (Cmax) of DTG was assessed using a population PK modeling approach. Blood samples for the determination of plasma DTG concentration were collected at the following time points: pre-dose and 1-3 hours (hrs) post-dose on Day 8; pre-dose and within a post-dose window (1-3 hours or 4-12 hours) on Day 28 and Week 24. For Day 8 PK, only samples collected from participants randomized to the active DTG arm were analyzed. Results from these PK parameters will be reported separately.

  • Plasma DTG Pre-dose Concentration (C0) at Day 8, Day 28, and Week 24; and Average DTG C0 (C0 Avg) at Week 24 [ Time Frame: Day 8, Day 28, and Week 24 ] [ Designated as safety issue: No ]
    Blood samples for the determination of plasma DTG pre-dose concentration were collected pre-dose on Day 8, Day 28, and Week 24. For Day 8 PK, only samples collected from participants randomized to the active DTG arm were analyzed. C0 Avg was calculated at Week 24 as the mean of the concentration at Day 8, Day 28, and Week 24

  • Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Defined Virologic Failure (PDVF), as a Measure of Genotypic Resistance [ Time Frame: From the first dose of study medication until early withdrawal or through the Day 8 analysis data cut-off date (average of 96 study days) ] [ Designated as safety issue: No ]
    For participants meeting one of the criteria for PDVF, plasma samples collected at the time point of virologic failure were tested to evaluate any potential genotypic and/or phenotypic evolution of resistance. PDVF was defined as (A) Virologic Non-response: a decrease in plasma HIV-1 RNA of <1 log10 copies/mL by Day 28, with subsequent confirmation, unless plasma HIV-1 RNA is <400 copies/mL; confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24 or (B) Virologic Rebound: confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL; confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL.Treatment-emergent IN mutations are those detected at the time of PDVF but not at Baseline.

  • Number of Participants With the Indicated Fold Increase in Fold Change (FC) in the 50% Inhibitory Concentration Relative to Wild-type Virus for DTG (i.e. PDVF FC/Baseline FC Ratio) at the Time of PDVF, as a Measure of Phenotypic Resistance [ Time Frame: From the first dose of study medication until early withdrawal or through the Day 8 analysis data cut-off date (average of 96 study days) ] [ Designated as safety issue: No ]
    For participants meeting one of the criteria for PDVF, plasma samples collected at the time point of virologic failure were tested to evaluate any potential genotypic and/or phenotypic evolution of resistance. 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 was defined as (A) Virologic Non-response: a decrease in plasma HIV-1 RNA of <1 log10 copies/mL by Day 28, with subsequent confirmation, unless plasma HIV-1 RNA is <400 copies/mL; confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24 or (B) Virologic Rebound: confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL; confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL.


Enrollment: 30
Study Start Date: April 2012
Estimated Study Completion Date: June 2015
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: dolutegravir 50mg twice daily
Active dolutegravir plus failing background regimen (Day 1 to Day 7)
Drug: dolutegravir 50 mg twice daily
Active dolutegravir plus failing background regimen (Day 1 to Day 7)
Other Name: GSK1349572
Experimental: dolutegravir placebo twice daily
Dolutegravir placebo plus failing background regimen (Day 1 to Day 7)
Drug: dolutegravir placebo twice daily
Dolutegravir placebo plus failing background regimen (Day 1 to Day 7)
Other Name: GSK1349572 Placebo
Experimental: Open-label dolutegravir 50mg twice daily
Open label dolutegravir plus optimized background regimen (From Day 8)
Drug: Open-label dolutegravir 50mg twice daily
Open label dolutegravir plus optimized background regimen (from Day 8)
Other Name: GSK1349572

Detailed Description:

Study ING116529 is a multicenter, randomized, study with an initial 7 day placebo-controlled, functional monotherapy phase to assess the antiviral activity and safety of a dolutegravir (DTG, GSK1349572) containing regimen in HIV-1 infected, ART-experienced adults with virological failure on an integrase inhibitor (INI) containing regimen.

Subjects must have evidence of genotypic resistance to raltegravir [RAL] or elvitegravir [ELV] at Screening and documented current or historical genotypic or phenotypic resistance to at least two other antiretroviral therapy drug classes.

The study is designed to provide an accurate measure of the intrinsic antiviral activity of DTG 50mg twice daily versus placebo both administered with the current failing regimen in a randomised double-blind phase to Day 8. This will be followed by an open label phase with all subjects receiving DTG 50mg twice daily with an optimized background regimen (containing at least one fully active drug) until subjects no longer derive clinical benefit or until DTG is locally available. Thirty subjects will be randomized (1:1) to receive either DTG 50mg BID (Arm A) or Placebo (Arm B) with the current failing regimen for 7 days (RAL or ELV should be discontinued prior to dosing at Day 1). At Day 8, subjects from both arms will enter an open label phase and receive open label DTG 50mg BID with an optimized background regimen containing at least one fully active drug The primary analysis will be conducted after the last subject enrolled has completed the randomised, double-blind phase at Day 8. Additional analyses may be performed prior to study closure when all ongoing subjects transition to locally available commercial DTG.

  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 ≥1000 copies/mL
  • ART-experienced, INI-experienced, DTG naïve
  • Current virological failure on raltegravir (RAL) or elvitegravir (ELV) regimen
  • The subject's HIV-1 shows genotypic resistance to RAL or ELV at Screening
  • Subject has been on stable ART for at least one month prior to Screening and through Day 1(with exceptions for ETV, EFV and NVP that can be interrupted within 14 days of Day 1, see Exclusion Criterion)
  • Documented resistance to at least one drug from each of two or more of any approved classes of ART other than integrase inhibitors
  • 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 (less than or equal to 3 months) 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 in vitro/vivo activity against HIV-1 within 28 days of first dose of investigational product (with the exception of entecavir if required for Hep B treatment)
  • Treatment with etravirine, efavirenz, or nevirapine within 14 days of Day 1(etravirine may be used if coadministered with lopinavir/ritonavir or darunavir/ritonavir)
  • Treatment with tipranivir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir within 28 days prior to Screening
  • Exposure to an experimental drug or vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, which ever is longer, prior to the first dose of IP.
  • Any acute or verified Grade 4 laboratory abnormality (with the exception of Grade 4 lipids) 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
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: NCT01568892

  Hide Study Locations
Locations
United States, Arkansas
GSK Investigational Site
Little Rock, Arkansas, United States, 72207
United States, California
GSK Investigational Site
Bakersfield, California, United States, 93301
GSK Investigational Site
Beverly Hills, California, United States, 90211
GSK Investigational Site
Los Angeles, California, United States, 90069
GSK Investigational Site
San Diego, California, United States, 92103-8208
United States, Connecticut
GSK Investigational Site
Norwalk, Connecticut, United States, 06850
United States, District of Columbia
GSK Investigational Site
Washington, District of Columbia, United States, 20009
GSK Investigational Site
Washington, District of Columbia, United States, 20007
United States, Florida
GSK Investigational Site
Fort Lauderdale, Florida, United States, 33316
GSK Investigational Site
Fort Pierce, Florida, United States, 34982
GSK Investigational Site
Orlando, Florida, United States, 32803
United States, Georgia
GSK Investigational Site
Augusta, Georgia, United States, 30912
GSK Investigational Site
Savannah, Georgia, United States, 31401
United States, Illinois
GSK Investigational Site
Maywood, Illinois, United States, 60153
United States, Massachusetts
GSK Investigational Site
Boston, Massachusetts, United States, 02115
United States, New Jersey
GSK Investigational Site
Hillsborough, New Jersey, United States, 08844
United States, New York
GSK Investigational Site
Bronx, New York, United States, 10467
GSK Investigational Site
Buffalo, New York, United States, 14215
GSK Investigational Site
New York, New York, United States, 10011
GSK Investigational Site
Valhalla, New York, United States, 10595
United States, North Carolina
GSK Investigational Site
Durham, North Carolina, United States, 27710
United States, Pennsylvania
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19140
United States, Texas
GSK Investigational Site
Austin, Texas, United States, 78705
GSK Investigational Site
Dallas, Texas, United States, 75246
United States, Virginia
GSK Investigational Site
Annandale, Virginia, United States, 22003
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: NCT01568892     History of Changes
Other Study ID Numbers: 116529
Study First Received: March 29, 2012
Results First Received: August 15, 2013
Last Updated: January 2, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by ViiV Healthcare:
ART-experienced
GSK1349572
Integrase inhibitor resistance
Dolutegravir

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

ClinicalTrials.gov processed this record on October 29, 2014