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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01449929
First received: October 6, 2011
Last updated: March 27, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: dolutegravir 50 mg OAD
Drug: darunavir 800mg OAD
Drug: ritonavir 100mg OAD
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Percentage of Participants With HIV-1 RNA <50 Copies/Milliliter (c/mL) at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <50 c/mL at Week 48 was assessed 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).


Secondary Outcome Measures:
  • Time to Virologic Suppression (<50 Copies/mL) Through Week 48 [ Time Frame: From Baseline through Week 48 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <400 c/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <400 c/mL at Week 48 was assessed 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).

  • Change From Baseline in Plasma HIV-1 RNA (log10 c/mL) at Weeks 4, 8, 12, 16, 24, 36 and 48 [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 24, 36 and 48 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in CD4+ and CD8+ Cell Counts [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 36 and 48 for CD4+ and Baseline and Weeks 4, 12, 24 and 48 for CD8+ ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Week 48 ] [ 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).

  • Change From Baseline in Fasting Low-density Lipoprotein (LDL) Cholesterol Through Week 48 [ Time Frame: From Baseline through Week 48 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Grade 2 or Higher Abnormalities in Fasting LDL Cholesterol Through Week 48 [ Time Frame: From Baseline through Week 48 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With the Indicated Grade 3 and Grade 4 Maximum Post-Baseline Chemistry and Hematology Laboratory Toxicities [ Time Frame: From Baseline through Week 48 ] [ Designated as safety issue: No ]
    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.

  • 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) [ Time Frame: Baseline until PDVF up to Week 48 ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline, Week 4, Week 24, and Week 48 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in EQ-5D Utility Scores at Week 24 and Week 48 [ Time Frame: Baseline, Week 24, and Week 48 ] [ Designated as safety issue: No ]
    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. 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.

  • Change From Baseline in EQ-5D Thermometer Scores at Week 24 and Week 48 [ Time Frame: Baseline, Week 24, and Week 48 ] [ Designated as safety issue: No ]
    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.

  • Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Total Score at Week 4, Week 24, and Week 48 [ Time Frame: Week 4, Week 24, and Week 48 ] [ Designated as safety issue: No ]
    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.

  • Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Lifestyle/Ease Sub Score at Week 4, Week 24, and Week 48 [ Time Frame: Week 4, Week 24, and Week 48 ] [ Designated as safety issue: No ]
    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).

  • Human Immunodeficiency Virus Treatment Satisfaction Questionnaire (HIVTSQ) Convenience Score at Week 4, Week 24, and Week 48 [ Time Frame: Week 4, Week 24, and Week 48 ] [ Designated as safety issue: No ]
    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).


Enrollment: 488
Study Start Date: October 2011
Estimated Study Completion Date: March 2015
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: dolutegravir 50mg once daily (OAD)
in combination with either abacavir/lamivudine fixed dose combination tablet OAD or tenofovir disoproxil fumarate/emtricitabline fixed dose combination tablet OAD
Drug: dolutegravir 50 mg OAD
1 x 50 mg tablet OAD
Active Comparator: darunavir 800mg OAD in combination with ritonavir 100mg OAD
in combination with either abacavir/lamivudine fixed dose combination tablet OAD or tenofovir disoproxil fumarate/emtricitabline fixed dose combination tablet OAD
Drug: darunavir 800mg OAD
2 x 400mg tablets OAD
Drug: ritonavir 100mg OAD
1 x 100mg tablet OAD

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT01449929

Locations
United States, Florida
GSK Investigational Site
Vero Beach, Florida, United States, 32690
United States, Missouri
GSK Investigational Site
Kansas City, Missouri, United States, 64111
France
GSK Investigational Site
Montpellier Cedex 5, France, 34295
GSK Investigational Site
Nantes, France, 44093
GSK Investigational Site
Paris, France, 75018
GSK Investigational Site
Paris Cedex 10, France, 75475
GSK Investigational Site
Paris Cedex 20, France, 75970
GSK Investigational Site
Saint Denis Cedex 01, France, 93205
Germany
GSK Investigational Site
Freiburg, Baden-Wuerttemberg, Germany, 79106
GSK Investigational Site
Frankfurt, Hessen, Germany, 60590
GSK Investigational Site
Hamburg, Germany, 20246
Italy
GSK Investigational Site
Modena, Emilia-Romagna, Italy, 41150
GSK Investigational Site
Roma, Lazio, Italy, 00149
GSK Investigational Site
Milano, Lombardia, Italy, 20142
GSK Investigational Site
Milano, Lombardia, Italy, 20127
GSK Investigational Site
Torino, Piemonte, Italy, 10149
Romania
GSK Investigational Site
Bucharest, Romania, 030303
GSK Investigational Site
Bucharest, Romania, 021105
GSK Investigational Site
Constanta, Romania, 900708
Russian Federation
GSK Investigational Site
Krasnodar, Russian Federation, 350015
GSK Investigational Site
Moscow, Russian Federation, 105275
GSK Investigational Site
Saratov, Russian Federation, 410009
GSK Investigational Site
St. Petersburg, Russian Federation, 196645
GSK Investigational Site
Volgograd, Russian Federation, 400040
Spain
GSK Investigational Site
Badalona, Spain, 08916
GSK Investigational Site
Barcelona, Spain, 08907
GSK Investigational Site
Barcelona, Spain, 08036
GSK Investigational Site
Madrid, Spain, 28041
GSK Investigational Site
Sevilla, Spain, 41013
Switzerland
GSK Investigational Site
Bern, Switzerland, 3010
GSK Investigational Site
Lausanne, Switzerland, 1011
GSK Investigational Site
Zurich, Switzerland, CH-8091
Sponsors and Collaborators
ViiV Healthcare
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare
  More Information

No publications provided by ViiV Healthcare

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT01449929     History of Changes
Other Study ID Numbers: 114915
Study First Received: October 6, 2011
Results First Received: December 12, 2013
Last Updated: March 27, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
ritonavir
HIV
HAART
darunavir
antiretroviral
dolutegravir
GSK1349572

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

ClinicalTrials.gov processed this record on September 30, 2014