Clinical trial NCT01449929: Dolutegravir Compared to Darunavir/Ritonavir , Each in Combination With Dual Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in ART-naive Subjects
Official title: A Phase IIIb, Randomized, Open-label Study of the Safety and Efficacy of GSK1349572 (Dolutegravir, DTG) 50 mg Once Daily Compared to Darunavir/Ritonavir (DRV/r) 800 mg/100 mg Once Daily Each Administered With Fixed-dose Dual Nucleoside Reverse Transcriptase Inhibitor Therapy Over 96 Weeks in HIV-1 Infected Antiretroviral naïve Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus
Keywords: ritonavir
HIV
HAART
darunavir
antiretroviral
dolutegravir
GSK1349572
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2011-10-10
Enrollment: 488
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will be conducted in approximately 468 HIV-1 infected antiretroviral therapy (ART)-naïve subjects. Subjects will be randomized 1:1 to receive dolutegravir (DTG) 50 mg once daily (approximately 234 subjects) or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily (approximately 234 subjects), each in combination with fixed-dose dual nucleoside reverse transriptase inhibitor (NRTI) therapy (either abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). Subjects will be stratified by screening HIV-1 RNA and background NRTI selection. The primary analysis will take place after the last subject completes 48 weeks on therapy; an additional analysis will be conducted after the last subject completes Week 96 on study.

Detailed description: ING114915 is a Phase IIIb randomized, open-label, active-controlled, multicentre, parallel group, fully-powered non-inferiority study. The study will be conducted in approximately 468 HIV-1 infected ART-naïve subjects. Subjects will be randomized 1:1 to receive DTG 50 mg once daily (approximately 234 subjects) or DRV/r 800 mg/100 mg once daily (approximately 234 subjects), each in combination with fixed-dose dual NRTI therapy (either ABC/3TC or TDF/FTC). The primary analysis will take place after the last subject completes 48 weeks on therapy; an additional analysis will be conducted after the last subject completes Week 96 on study.

Subjects who fulfil eligibility requirements will be randomized 1:1 to receive DTG 50 mg once daily or DRV/r 800 mg/100 mg once daily. In order to achieve balance across the two treatment groups of the study, randomization will be stratified by: screening plasma HIV-1 RNA \>/ 100,000 copies/mL (c/mL) or \> 100,000 c/mL and background dual NRTI (ABC/3TC or TDF/FTC) The DTG and DRV/r doses will be administered in an open-label fashion throughout the study.

Subjects randomized to receive DTG and who successfully complete 96 weeks of treatment will continue to have access to DTG until either it is locally approved and commercially available, the patient no longer derives clinical benefit, the patient meets a protocol-defined reason for discontinuation or until development of DTG is terminated. Subjects randomized to the DRV/r arm will receive DRV/r through their Week 96 visit, after which they will be discontinued from the study and will need to make alternative arrangements to access antiretroviral medication. All subjects will receive background dual-NRTI therapy through their Week 96 visit.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infected adults greater than or equal to 18 years of age. Females are eligible to enter and participate in the study if she is (1) non-childbearing potential, (2) child bearing potential with negative pregnancy test at screening and Day 1 and agrees to use protocol-specified methods of birth control while on study.
* HIV-1 infection with a screening plasma HIV-1 RNA greater than or equal to 1000copies/mL
* Antiretroviral-naïve (less than or equal to 10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection)
* Signed and dated written informed consent is obtained from the subject or the subject's legal representative prior to screening

Exclusion Criteria:

* Women who are pregnant or breastfeeding
* Any evidence of an active Centers for Disease and Prevention Control (CDC) Category C disease \[CDC, 1993\], except cutaneous Kaposi's sarcoma not requiring systemic therapy
* Subjects with moderate to severe hepatic impairment (Class B or C) as determined by Child-Pugh classification
* Anticipated need for Hepatitis C virus (HCV) therapy during the study
* History or presence of allergy or intolerance to the study drugs or their components or drugs of their class
* History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject
* 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; any immunomodulators
* Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 in vitro within 28 days of first dose of investigational product
* 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 investigational product
* Any evidence of primary viral resistance based on the presence of any major resistance-associated mutation \[IAS-USA, 2010\] in the Screening result or, if known, any historical resistance test result
* Any verified Grade 4 laboratory abnormality. 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 is exclusionary
* Alanine aminotransferase (ALT) greater than 5 times the upper limit of normal
* ALT greater than 3 times the upper limit of normal and bilirubin greater than or equal to 1.5 times the upper limit of normal (with greater than 35% direct bilirubin)
* Subject has creatinine clearance of less than 50 mL/min via Cockroft-Gault method
* Recent history (less than or equal to 3 months) of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding

Primary outcomes:
measure: Percentage of Participants With Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 48
timeFrame: Week 48
Secondary outcomes:
measure: Time to Virologic Suppression (<50 Copies/mL) Through Week 48
timeFrame: From Baseline through Week 48
measure: Percentage of Participants With Plasma HIV-1 RNA <400 c/mL at Week 48
timeFrame: Week 48
measure: Change From Baseline in Plasma HIV-1 RNA (log10 c/mL) at Weeks 4, 8, 12, 16, 24, 36 and 48
timeFrame: Baseline, Weeks 4, 8, 12, 16, 24, 36 and 48
measure: Change From Baseline in CD4+ and CD8+ Cell Counts
timeFrame: Baseline and Weeks 4, 8, 12, 16, 36 and 48 for CD4+ and Baseline and Weeks 4, 12, 24 and 48 for CD8+
measure: Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shift to CDC Class C, or New CDC Class C or Death at Week 48
timeFrame: Week 48
measure: Change From Baseline in Fasting Low-density Lipoprotein (LDL) Cholesterol Through Week 48
timeFrame: From Baseline through Week 48
measure: Percentage of Participants With Grade 2 or Higher Abnormalities in Fasting LDL Cholesterol Through Week 48
timeFrame: From Baseline through Week 48
measure: Number of Participants With the Indicated Grade 3 and Grade 4 Maximum Post-Baseline Chemistry and Hematology Laboratory Toxicities
timeFrame: From Baseline through Week 48
measure: Number of Participants (Par.) With Detectable Virus That Has Genotypic or Phenotypic Evidence of Treatment-emergent Resistance to DTG, DRV+RTV and Other On-study ART at Time of Protocol Defined Virology Failure (PDVF)
timeFrame: Baseline until PDVF up to Week 48
measure: Change From Baseline in Acquired Immune Deficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Symptom Distress Module (SDM) Bother Score at Week 4, Week 24, and Week 48
timeFrame: Baseline, Week 4, Week 24, and Week 48
measure: Change From Baseline in European Quality of Life -5 Dimensions (EQ-5D) Utility Scores at Week 24 and Week 48
timeFrame: Baseline, Week 24, and Week 48
measure: Change From Baseline in EQ-5D Thermometer Scores at Week 24 and Week 48
timeFrame: Baseline, Week 24, and Week 48
measure: Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Total Score at Week 4, Week 24, and Week 48
timeFrame: Week 4, Week 24, and Week 48
measure: Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Lifestyle/Ease Sub Score at Week 4, Week 24, and Week 48
timeFrame: Week 4, Week 24, and Week 48
measure: Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Convenience Score at Week 4, Week 24, and Week 48
timeFrame: Week 4, Week 24, and Week 48
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
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: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
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: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Daytona Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Vero Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Decatur
country: United States
facility: GSK Investigational Site
state: Georgia
city: Macon
country: United States
facility: GSK Investigational Site
state: Georgia
city: Savannah
country: United States
facility: GSK Investigational Site
state: Georgia
city: Springfield
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Winston-Salem
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cincinnati
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: Providence
country: United States
facility: GSK Investigational Site
state: Rhode Island
city: Dallas
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: Longview
country: United States
facility: GSK Investigational Site
state: Texas
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
city: Montpellier Cedex 5
country: France
facility: GSK Investigational Site
city: Nantes
country: France
facility: GSK Investigational Site
city: Paris Cedex 10
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: Saint Denis Cedex 01
country: France
facility: GSK Investigational Site
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Modena
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Milano
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: Ponce
country: Puerto Rico
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Constanta
country: Romania
facility: GSK Investigational Site
city: Krasnodar
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Saratov
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Volgograd
country: Russian Federation
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Bern
country: Switzerland
facility: GSK Investigational Site
city: Lausanne
country: Switzerland
facility: GSK Investigational Site
city: Zurich
country: Switzerland
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, Kulagin V, Givens N, de Oliveira CF, Brennan C; FLAMINGO study team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015 Apr;2(4):e127-36. doi: 10.1016/S2352-3018(15)00027-2. Epub 2015 Mar 10.
citation: Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, Pokrovskiy V, Fehr J, Ortiz R, Saag M, Harris J, Brennan C, Fujiwara T, Min S; ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014 Jun 28;383(9936):2222-31. doi: 10.1016/S0140-6736(14)60084-2. Epub 2014 Apr 1.