Clinical trial NCT01328041: A Study to Assess Dolutegravir in HIV-infected Subjects With Treatment Failure on an Integrase Inhibitor Containing Regimen.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus
Keywords: GSK1349572
resistance to raltegravir or elvitegravir
Integrase inhibitor
ART-experienced
dolutegravir
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Shionogi
name: GlaxoSmithKline
First posted: 2011-04-04
Enrollment: 183
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Mean Change From Baseline in Plasma HIV-1 RNA at Day 8
timeFrame: Baseline and Day 8
measure: Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 24
timeFrame: Week 24
measure: Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48
timeFrame: Week 48
measure: Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)
timeFrame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
measure: Number of Participants With Adverse Events of the Indicated Severity, Per the Division of Acquired Immune Deficiency Syndrome (DAIDS) Grading Scale
timeFrame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
measure: Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade
timeFrame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
measure: Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade
timeFrame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Secondary outcomes:
measure: 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, 24, 32, 40, and 48
timeFrame: Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
measure: Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL From Week 48 Every 12 Weeks up to Study Completion
timeFrame: From Week 48 every 12 weeks up to study completion.
measure: Mean Change From Baseline in Plasma HIV-1 RNA at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study Completion
timeFrame: Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study completion (Up to Week 180)
measure: Absolute Values for CD4+ Cell Counts at Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 and for CD8+ Cell Counts at Baseline and Weeks 4, 12, 24, and 48
timeFrame: Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
measure: Median Change From Baseline in CD4+ Cell Counts at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks Until Study Completion
timeFrame: Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180. v
measure: Ratio of CD4+/CD8+ Cell Count at Baseline and Weeks 4, 12, 24, and 48
timeFrame: Baseline; Weeks 4, 12, 24, and 48
measure: Number of Participants With HIV-1 Disease Progression (Acquired Immune Deficiency Syndrome [AIDS] or Death)
timeFrame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
measure: Cmax and Ctau of DTG
timeFrame: Day 8, Week 4, and Week 24
measure: AUC(0-tau) and AUC(0-24) of DTG
timeFrame: Day 8, Week 4, and Week 24
measure: C0 Assessment of DTG
timeFrame: Day 8, Week 4, and Week 24
measure: 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
timeFrame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
measure: 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
timeFrame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: GSK Investigational Site
state: California
city: Fountain Valley
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
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: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: New Haven
country: United States
facility: GSK Investigational Site
state: Connecticut
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: Miami Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Lafayette
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Jackson
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Newark
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Albany
country: United States
facility: GSK Investigational Site
state: New York
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
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: 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: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Toledo
country: United States
facility: GSK Investigational Site
state: Ohio
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Providence
country: United States
facility: GSK Investigational Site
state: Rhode Island
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Annandale
country: United States
facility: GSK Investigational Site
state: Virginia
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
city: Bruxelles
country: Belgium
facility: GSK Investigational Site
city: Liege
country: Belgium
facility: GSK Investigational Site
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Aulnay-sous-Bois
country: France
facility: GSK Investigational Site
city: Bobigny
country: France
facility: GSK Investigational Site
city: Bordeaux
country: France
facility: GSK Investigational Site
city: Garches
country: France
facility: GSK Investigational Site
city: Gonesse cedex
country: France
facility: GSK Investigational Site
city: Marseille
country: France
facility: GSK Investigational Site
city: Marseille
country: France
facility: GSK Investigational Site
city: Nice
country: France
facility: GSK Investigational Site
city: Orléans Cedex 2
country: France
facility: GSK Investigational Site
city: Paris Cedex 10
country: France
facility: GSK Investigational Site
city: Paris Cedex 13
country: France
facility: GSK Investigational Site
city: Paris cedex 14
country: France
facility: GSK Investigational Site
city: Paris cedex 15
country: France
facility: GSK Investigational Site
city: Paris Cedex 20
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Genova
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Bergamo
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Torino
country: Italy
facility: GSK Investigational Site
state: Piemonte
city: Bagno a Ripoli (FI)
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Firenze
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Amadora
country: Portugal
facility: GSK Investigational Site
city: Coimbra
country: Portugal
facility: GSK Investigational Site
city: Lisboa
country: Portugal
facility: GSK Investigational Site
city: Lisboa
country: Portugal
facility: GSK Investigational Site
city: Lisboa
country: Portugal
facility: GSK Investigational Site
city: Alicante
country: Spain
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: La Coruña
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A, Poizot-Martin I, Richmond G, Soriano V, Ait-Khaled M, Fujiwara T, Huang J, Min S, Vavro C, Yeo J; VIKING Study Group. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis. 2013 Mar 1;207(5):740-8. doi: 10.1093/infdis/jis750. Epub 2012 Dec 7.
citation: Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, Molina JM, Chas J, Durant J, Moreno S, Doroana M, Ait-Khaled M, Huang J, Min S, Song I, Vavro C, Nichols G, Yeo JM; VIKING-3 Study Group. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014 Aug 1;210(3):354-62. doi: 10.1093/infdis/jiu051. Epub 2014 Jan 19.