Clinical trial NCT01568892: Study Assessing Dolutegravir in HIV-1 Infected Subjects With Virus Resistant to Raltegravir and/or Elivitegravir
Official title: A Phase III Randomized, Double-blind Study to Demonstrate the Antiviral Activity of Dolutegravir (DTG) 50 mg Twice Daily Versus Placebo Both Co-Administered With a Failing Antiretroviral Regimen Over Seven Days, Followed by an Open Label Phase With All Subjects Receiving DTG 50 mg Twice Daily Co-administered With an Optimised Background Regimen (OBR) in HIV-1 Infected, Integrase Inhibitor Therapy-Experienced and Resistant, Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: ART-experienced
GSK1349572
Integrase inhibitor resistance
Dolutegravir
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Shionogi
name: GlaxoSmithKline
First posted: 2012-04-02
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Mean Change From Baseline in Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) at Day 8
timeFrame: Baseline and Day 8
Secondary outcomes:
measure: Absolute Values in Plasma HIV-1 RNA Over Time
timeFrame: Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84
measure: Mean Change From Baseline in Plasma HIV-1 RNA Over Time
timeFrame: Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84
measure: Number of Participants With Plasma HIV-1 RNA <50 c/mL Over Time
timeFrame: Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40 and 48
measure: Number of Participants With Plasma HIV-1 RNA <400 c/mL Over Time
timeFrame: Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40 and 48
measure: Absolute Values in Cluster of Differentiation 4+ (CD4+) Cell Counts Over Time
timeFrame: Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84
measure: Median Change From Baseline in CD4+ Cell Counts Over Time
timeFrame: Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84
measure: Absolute Values in Cluster of Differentiation 8+ (CD8+) Cell Counts Over Time
timeFrame: Baseline; Day 28; Weeks 12, 24, and 48
measure: Median Change From Baseline in CD8+ Cell Counts Over Time
timeFrame: Baseline; Day 28; Weeks 12, 24, and 48
measure: Number of Participants With the Indicated Type of HIV-1 Disease Progression (Acquired Immunodeficiency Syndrome [AIDS] or Death [DT])
timeFrame: From the day of the first dose of study drug until early withdrawal or the Week 48 analysis cut-off date (median of 55 study weeks)
measure: Number of Participants With Any Adverse Event (Serious and Non-serious) of the Indicated Grade
timeFrame: From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
measure: Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade
timeFrame: From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
measure: Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade
timeFrame: From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
measure: AUC(0-tau) of DTG
timeFrame: Day 8, Day 28, and Week 24
measure: Cmax of DTG
timeFrame: Day 8, Day 28, and Week 24
measure: Plasma DTG Pre-dose Concentration (C0) at Day 8, Day 28, and Week 24; and Average DTG C0 (C0 Avg) at Week 24
timeFrame: Day 8, Day 28, and Week 24
measure: 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
timeFrame: From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
measure: 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
timeFrame: From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
measure: Number of Participants Who Discontinued Study Treatment Due to AEs
timeFrame: From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
measure: Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
timeFrame: Up to Week 24
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline in Heart Rate
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline in Albumin Level
timeFrame: Baseline, Week 24 and 48
measure: Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Creatine Kinase
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
measure: Change From Baseline in Total Bilirubin (T. Bil) and Creatinine Levels
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
measure: Change From Baseline in Cholesterol, Chloride, Carbon Dioxide (CO2)/Bicarbonate (HCO3), Glucose, High Density Lipoprotein Cholesterol, Potassium, Low Density Lipoprotein (LDL) Cholesterol, Sodium, Phosphorus, Triglycerides and Urea/Blood Urea Nitrogen
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
measure: Change From Baseline in Creatinine Clearance
timeFrame: Baseline, Day 8, Day 28, Week 8, Week 16, Week 24, Week 32 and Week 48
measure: Change From Baseline in Lipase Levels
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
measure: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet and White Blood Cell (WBC) Count
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
measure: Change From Baseline in Hemoglobin Level
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
measure: Change From Baseline in Hematocrit Level
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
measure: Change From Baseline in Mean Corpuscle Volume
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
measure: Change From Baseline in Red Blood Cell Count
timeFrame: Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: GSK Investigational Site
state: Arkansas
city: Bakersfield
country: United States
facility: GSK Investigational Site
state: California
city: Beverly Hills
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: San Diego
country: United States
facility: GSK Investigational Site
state: California
city: Norwalk
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Pierce
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Savannah
country: United States
facility: GSK Investigational Site
state: Georgia
city: Maywood
country: United States
facility: GSK Investigational Site
state: Illinois
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Hillsborough
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Buffalo
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Valhalla
country: United States
facility: GSK Investigational Site
state: New York
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Annandale
country: United States
facility: GSK Investigational Site
state: Virginia
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Akil B, Blick G, Hagins DP, Ramgopal MN, Richmond GJ, Samuel RM, Givens N, Vavro C, Song IH, Wynne B, Ait-Khaled M; VIKING-4 study team. Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study. Antivir Ther. 2015;20(3):343-8. doi: 10.3851/IMP2878. Epub 2014 Oct 16.