Dolutegravir Compared to Darunavir/Ritonavir , Each in Combination With Dual Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in ART-naive Subjects

Infection, Human Immunodeficiency Virus Clinical Trial

— FLAMINGO  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01449929
• Other study ID #: 114915
• Status: Completed
• Phase: Phase 3
• First received: October 6, 2011
• Last updated: December 14, 2017
• Start date: October 31, 2011
• Est. completion date: December 26, 2016

Study information

• Verified date: October 2017
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 488
• Est. completion date: December 26, 2016
• Est. primary completion date: April 22, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Immunologic Deficiency Syndromes
• Infection, Human Immunodeficiency Virus

Intervention

Drug:
• dolutegravir 50 mg OAD
1 x 50 mg tablet OAD
• darunavir 800mg OAD
2 x 400mg tablets OAD
• ritonavir 100mg OAD
1 x 100mg tablet OAD

Locations

Country	Name	City	State
France	GSK Investigational Site	Montpellier Cedex 5
France	GSK Investigational Site	Nantes
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris Cedex 10
France	GSK Investigational Site	Paris Cedex 20
France	GSK Investigational Site	Saint Denis Cedex 01
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Hamburg
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Modena	Emilia-Romagna
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Torino	Piemonte
Puerto Rico	GSK Investigational Site	Ponce
Puerto Rico	GSK Investigational Site	San Juan
Puerto Rico	GSK Investigational Site	San Juan
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Constanta
Russian Federation	GSK Investigational Site	Krasnodar
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Saratov
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	Volgograd
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Sevilla
Switzerland	GSK Investigational Site	Bern
Switzerland	GSK Investigational Site	Lausanne
Switzerland	GSK Investigational Site	Zurich
United States	GSK Investigational Site	Augusta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Daytona Beach	Florida
United States	GSK Investigational Site	Decatur	Georgia
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Kansas City	Missouri
United States	GSK Investigational Site	Longview	Texas
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Macon	Georgia
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	Norwalk	Connecticut
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Providence	Rhode Island
United States	GSK Investigational Site	Savannah	Georgia
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Springfield	Massachusetts
United States	GSK Investigational Site	Tampa	Florida
United States	GSK Investigational Site	Vero Beach	Florida
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
ViiV Healthcare	GlaxoSmithKline

Countries where clinical trial is conducted

United States,  France,  Germany,  Italy,  Puerto Rico,  Romania,  Russian Federation,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 48	Assessment was done using Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm.This algorithm treated all participants without HIV-1 RNA data at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the snapshot window (Week 48 +/- 6 weeks). Modified Intent-To-Treat Exposed (mITT-E) Population:all randomized participants who received at least one dose of investigational product	Week 48
Secondary	Time to Virologic Suppression (<50 Copies/mL) Through Week 48	The time to viral suppression (i.e. first viral load value <50 copies/mL) through Week 48 was derived and summarized using Kaplan-Meier plots. Participants who withdrew for any reason without having suppressed prior to the analysis were censored. Confidence intervals were estimated using the Brookmeyer-Crowley method.	From Baseline through Week 48
Secondary	Percentage of Participants With Plasma HIV-1 RNA <400 c/mL at Week 48	The percentage of participants with Plasma HIV-1 RNA <400 c/mL at Week 48 was assessed MSDF, as codified by the FDA "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA data at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the snapshot window (Week 48 +/- 6 weeks).	Week 48
Secondary	Change From Baseline in Plasma HIV-1 RNA (log10 c/mL) at Weeks 4, 8, 12, 16, 24, 36 and 48	Change from Baseline in plasma HIV-1 RNA (log10 c/mL) was assessed at Weeks 4, 8, 12, 16, 24, 36 and 48 . Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits, so the overall number of participants analyzed reflects everyone in the mITT-E Population.	Baseline, Weeks 4, 8, 12, 16, 24, 36 and 48
Secondary	Change From Baseline in CD4+ and CD8+ Cell Counts	Change from Baseline in CD4+ cell counts was assessed at Weeks 4, 8, 12, 16, 36 and 48. Change from Baseline in CD8+ cell counts was assessed at Weeks 4, 12, 24 and 48. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits and parameters, so the overall number of participants analyzed reflects everyone in the mITT-E Population.	Baseline and Weeks 4, 8, 12, 16, 36 and 48 for CD4+ and Baseline and Weeks 4, 12, 24 and 48 for CD8+
Secondary	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	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).	Week 48
Secondary	Change From Baseline in Fasting Low-density Lipoprotein (LDL) Cholesterol Through Week 48	Fasting LDL cholesterol change from Baseline was analyzed. Values represented are for adjusted means. Estimates are calculated from a repeated measures model including the following covariates: treatment, visit, Baseline plasma HIV-1 RNA, background dual NRTI therapy, Baseline LDL cholesterol, treatment*visit interaction and Baseline LDL cholesterol*visit interaction. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the specified time points were analyzed.	From Baseline through Week 48
Secondary	Percentage of Participants With Grade 2 or Higher Abnormalities in Fasting LDL Cholesterol Through Week 48	Hematology and clinical chemistry data were summarized according to the division of AIDS (DAIDS) table for grading the Severity of adverse events, version 1.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for which an increase in fasting LDL cholesterol to Grade 2 or higher occurred. Only those participants with data available at the specified time points were analyzed.	From Baseline through Week 48
Secondary	Number of Participants With the Indicated Grade 3 and Grade 4 Maximum Post-Baseline Chemistry and Hematology Laboratory Toxicities	Hematology and clinical chemistry data were summarized according to the division of AIDS (DAIDS) table for grading the Severity of adverse events, version 1.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred.	From Baseline through Week 48
Secondary	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)	An assessment was made of every change across all amino acids within the integrase (IN), reverse transcriptase (RT), and Protease (PRO) encoding region at Baseline and at time of suspected PDVF. PDVF is defined as the confirmed plasma HIV-1 RNA >200 c/mL >=Week 24. PDVF Genotypic Population included all participants in the mITT-E population with available on-treatment genotypic resistance data, at time of PDVF. Only those participants with data available at the specified time points were analyzed.	Baseline until PDVF up to Week 48
Secondary	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	SDM is a 20-item self-reported measure that addresses the presence and perceived distress linked to symptoms commonly associated with HIV or its treatment. Each item is rated from 0 to 4 where 0 (complete absence of symptom) and 4 (very bothersome symptom). Overall score calculated as the sum of the scores for each of the 20 items of the questionnaire and ranged from 0 (best health) and 80 (worst health). Values represented are for adjusted mean. Estimates are calculated from an ANCOVA model adjusting for age, sex, race, baseline viral load, background dual NRTI therapy and baseline symptom bother score. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A positive change from Baseline indicates a decline in a participant's quality of life over that period.	Baseline, Week 4, Week 24, and Week 48
Secondary	Change From Baseline in European Quality of Life -5 Dimensions (EQ-5D) Utility Scores at Week 24 and Week 48	The EQ-5D is a 5-question quality of life instrument that provides a utility score and visual analogue scale score that describes the participants' health status. The primary reason for including the EQ-5D is to elicit utility values for potential cost-effectiveness analysis for submission to health technology assessment agencies. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome. Values represented are for adjusted mean. Estimates are calculated from an ANCOVA model adjusting for age, sex, race, baseline viral load, background dual NRTI therapy and Baseline EQ-5D utility score. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline, Week 24, and Week 48
Secondary	Change From Baseline in EQ-5D Thermometer Scores at Week 24 and Week 48	The European Quality of Life -5 Dimensions (EQ-5D) is a 5-question quality of life instrument that provides a utility score and visual analogue scale score that describes the participants' health status. The primary reason for including the EQ-5D is to elicit utility values for potential cost-effectiveness analysis for submission to health technology assessment agencies. Thermometer score is based on a visual analogue scale (VAS) ranging from 100 (best imaginable health state) to 0 (worst imaginable health state).Values represented are for adjusted mean. Estimates are calculated from an ANCOVA model adjusting for age, sex, race, Baseline viral load, background dual NRTI therapy and Baseline EQ-5D thermometer score. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline, Week 24, and Week 48
Secondary	Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Total Score at Week 4, Week 24, and Week 48	Participant treatment satisfaction was measured using the self-reported scale (HIVTSQ), which consists of 10 items (1-satisfaction, 2-HIV control, 3-adverse effects, 4-level of demand, 5-convenience, 6-flexibility, 7-knowledge, 8-life habits, 9-recommendability, and 10-willingness to continue). Items are scored from 0 (very dissatisfied) to 6 (very satisfied), other than item 4, which has an inverted score from 6 (very demanding) to 0 (very undemanding). The treatment satisfaction score (range: 0-60) was the sum of the individual items. HIVTSQ mITT-E Population=Only participants from USA, France, Germany, Italy, Spain for whom valid translations were available from the mITT-E Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits, so the overall number of participants analyzed reflects everyone in the HIVTSQ mITT-E population.	Week 4, Week 24, and Week 48
Secondary	Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Lifestyle/Ease Sub Score at Week 4, Week 24, and Week 48	Participant treatment satisfaction was measured using the self-reported scale (HIVTSQ), which consists of 10 items (1-satisfaction, 2-HIV control, 3-adverse effects, 4-level of demand, 5-convenience, 6-flexibility, 7-knowledge, 8-life habits, 9-recommendability, and 10-willingness to continue). Items are scored from 0 (very dissatisfied) to 6 (very satisfied), other than item 4, which has an inverted score from 6 (very demanding) to 0 (very undemanding). The lifestyle/ease score is the sum of items 4, 5, 6, 7 and 8 (range: 0-30). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits, so the overall number of participants analyzed reflects everyone in the HIVTSQ mITT-E population.	Week 4, Week 24, and Week 48
Secondary	Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Convenience Score at Week 4, Week 24, and Week 48	Participant treatment satisfaction was measured using the self-reported scale (HIVTSQ), which consists of 10 items (1-satisfaction, 2-HIV control, 3-adverse effects, 4-level of demand, 5-convenience, 6-flexibility, 7-knowledge, 8-life habits, 9-recommendability, and 10-willingness to continue). Items are scored from 0 (very dissatisfied) to 6 (very satisfied), other than item 4, which has an inverted score from 6 (very demanding) to 0 (very undemanding). The convenience score is the score for item 5 (range: 0-6). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits, so the overall number of participants analyzed reflects everyone in the HIVTSQ mITT-E population.	Week 4, Week 24, and Week 48