A Trial Comparing GSK1349572 50mg Plus Abacavir/Lamivudine Once Daily to Atripla (Also Called The SINGLE Trial)

Infection, Human Immunodeficiency Virus I Clinical Trial

Official title:

A Randomized, Double-Blind Study of the Safety and Efficacy of GSK1349572 Plus Abacavir/Lamivudine Fixed-Dose Combination Therapy Administered Once Daily Compared to Atripla Over 96 Weeks in HIV-1 Infected Antiretroviral Therapy Naive Adult Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01263015
• Other study ID #: 114467
• Status: Completed
• Phase: Phase 3
• First received: December 16, 2010
• Last updated: March 8, 2018
• Start date: February 1, 2011
• Est. completion date: December 3, 2015

Study information

• Verified date: March 2018
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this trial is to assess the non-inferior antiviral activity of GSK1349572 50 mg plus Abacavir/Lamivudine once daily versus Efavirenz/Emtricitabine/Tenofovir disoproxil fumarate (ATRIPLA® a trade mark of Bristol-Myers Squibb and Gilead Sciences LLC) over 48 weeks; non-inferiority will also be tested at Week 96. This study will be conducted in HIV-1 infected ART-naïve adult subjects. Long term antiviral activity, tolerability, safety, and development of viral resistance will be evaluated.

Description:

ING114467 is a Phase 3 randomized, double-blind, double dummy, active-controlled, multicenter, study conducted in approximately 788 HIV-1 infected ART-naïve subjects. Subjects will be randomized 1:1 one of the following treatment arms:

GSK1349572 50 mg plus abacavir/lamivudine fixed-dose combination once daily (approximately 394 subjects)

OR

Atripla once daily (approximately 394 subjects)

Analyses will be conducted at 48 weeks and 96 weeks. Subjects randomized to receive GSK1349572 and who successfully complete 96 weeks of treatment will continue to have access to GSK1349572 plus abacavir/lamivudine fixed-dose combination through the study until it is locally available-as long as they continue to derive clinical benefit, until they meet a protocol-defined reason for discontinuation, or until development of the compound is terminated.

ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship

Recruitment information / eligibility

• Status: Completed
• Enrollment: 844
• Est. completion date: December 3, 2015
• Est. primary completion date: May 14, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Screening plasma HIV-1 RNA =1000 c/mL

• Antiretroviral-naïve (= 10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection)

• Ability to understand and sign a written informed consent form

• Willingness to use approved methods of contraception to avoid pregnancy (women of child bearing potential only)

• Age equal to or greater than 18 years

• A negative HLAB*5701 allele assessment

Exclusion Criteria:

• Women who are pregnant or breastfeeding;

• Active Center for Disease and Prevention Control (CDC) Category C disease

• Hepatic impairment

• HBV co-infection

• Anticipated need for HCV therapy during the study

• Allergy or intolerance to the study drugs or their components or drugs of their class

• Malignancy within the past 5 years

• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening

• Treatment with radiation therapy, cytotoxic chemotherapeutic agents or any immunomodulator within 28 days of Screening

• Exposure to an agent with documented activity against HIV-1 in vitro or an experimental vaccine or drug within 28 days of first dose of study medication

• Primary viral resistance in the Screening result

• Verified Grade 4 laboratory abnormality

• ALT >5 xULN

• ALT = 3xULN and bilirubin = 1.5xULN (with >35% direct bilirubin);

• Estimated creatinine clearance <50 mL/min

• Recent history (=3 months) of upper or lower gastrointestinal bleed

Related Conditions & MeSH terms

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

Intervention

Drug:
• Dolutegravir
Dolutegravir (also known as GSK1349572) 50 mg taken once daily
• Atripla
Atripla once daily on an empty stomach
• Abacavir/Lamivudine
taken once daily; also known as EPZICOM
• Abacavir/Lamivudine Placebo
matching placebo taken once daily
• Dolutegravir placebo
matching placebo taken once daily
• Atripla placebo
matching placebo taken once daily on an empty stomach

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Carlton	Victoria
Australia	GSK Investigational Site	Darlinghurst, Sydney	New South Wales
Australia	GSK Investigational Site	North Fitzroy	Victoria
Australia	GSK Investigational Site	Prahran	Victoria
Belgium	GSK Investigational Site	Antwerpen
Belgium	GSK Investigational Site	Bruxelles
Belgium	GSK Investigational Site	Gent
Belgium	GSK Investigational Site	Liege
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Vancouver	British Columbia
Canada	GSK Investigational Site	Vancouver	British Columbia
Canada	GSK Investigational Site	Winnipeg	Manitoba
Denmark	GSK Investigational Site	Hvidovre
Denmark	GSK Investigational Site	Koebenhavn
Denmark	GSK Investigational Site	Odense
France	GSK Investigational Site	Nice
France	GSK Investigational Site	Orléans Cedex 2
France	GSK Investigational Site	Paris Cedex 20
France	GSK Investigational Site	Saint Denis Cedex 01
France	GSK Investigational Site	Strasbourg cedex
France	GSK Investigational Site	Tourcoing cedex
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg
Italy	GSK Investigational Site	Bagno A Ripoli (FI)	Toscana
Italy	GSK Investigational Site	Bergamo	Lombardia
Italy	GSK Investigational Site	Genova	Liguria
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Ravenna	Emilia-Romagna
Italy	GSK Investigational Site	Roma	Lazio
Netherlands	GSK Investigational Site	Rotterdam
Netherlands	GSK Investigational Site	Rotterdam
Netherlands	GSK Investigational Site	Utrecht
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Constanta
Spain	GSK Investigational Site	(Móstoles) Madrid
Spain	GSK Investigational Site	Alcala de Henares
Spain	GSK Investigational Site	Alicante
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Basurto/Bilbao
Spain	GSK Investigational Site	Elche (Alicante)
Spain	GSK Investigational Site	Granada
Spain	GSK Investigational Site	Granollers (Barcelona)
Spain	GSK Investigational Site	La Laguna (Santa Cruz De Tenerife)
Spain	GSK Investigational Site	Logroño
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Málaga
Spain	GSK Investigational Site	Marid
Spain	GSK Investigational Site	Murcia
Spain	GSK Investigational Site	Oviedo	Asturias
Spain	GSK Investigational Site	Palma de Mallorca
Spain	GSK Investigational Site	Sabadell (Barcelona)
Spain	GSK Investigational Site	San Sebastián
Spain	GSK Investigational Site	Santiago de Compostela
Spain	GSK Investigational Site	Sevilla
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Vigo ( Pontevedra)
United Kingdom	GSK Investigational Site	Birmingham
United Kingdom	GSK Investigational Site	Liverpool
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Tooting, London
United Kingdom	GSK Investigational Site	Woolwich, London	London
United States	GSK Investigational Site	Augusta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Bakersfield	California
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Beverly Hills	California
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Bronx	New York
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Chicago	Illinois
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	Denver	Colorado
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Fort Lauderdale	Florida
United States	GSK Investigational Site	Fort Pierce	Florida
United States	GSK Investigational Site	Fort Worth	Texas
United States	GSK Investigational Site	Hobson City	Alabama
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Iowa City	Iowa
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	Little Rock	Arkansas
United States	GSK Investigational Site	Long Beach	California
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	Maywood	Illinois
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Miami Beach	Florida
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Newark	New Jersey
United States	GSK Investigational Site	Oakland	California
United States	GSK Investigational Site	Omaha	Nebraska
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	Salt Lake City	Utah
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Springfield	Massachusetts
United States	GSK Investigational Site	Valhalla	New York
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	West Palm Beach	Florida

Sponsors (3)

Lead Sponsor	Collaborator
ViiV Healthcare	GlaxoSmithKline, Shionogi

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Denmark,  France,  Germany,  Italy,  Netherlands,  Romania,  Spain,  United Kingdom, 

References & Publications (1)

Brinson C, Walmsley S, Arasteh K, et al. Dolutegravir treatment response and safety by key subgroups in treatment naive HIV-infected individuals. Published at: Conference on Retroviruses and Opportunistic Infections - 20th Annual; March 3-6, 2013; Atlanta, GA.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Subjects Responding Based on Plasma HIV-1 RNA <50 c/mL at Week 48	The percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 48 was assessed. Plasma samples were collected for the quantitative assessment of HIV-1 RNA based on the Missing, Switch, or Discontinuation equals Failure (MSDF) algorithm,as codified by the Food and Drug Administration's Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigationl product prior to the visit window) as non-responders, as well as participants who switched their concomitant antiretroviral therapy (ART) in certain scenarios. Since changes in ART were not permitted in this protocol, all such participants who changed ART were to be considered non-responders. Otherwise, virologic success or failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the visit of interest window.	Week 48
Secondary	Time to Viral Suppression (<50 c/mL)	Viral suppression is defined as the first viral load value<50 c/mL. The Kaplan-Meier method was used to estimate time to viral suppression, defined as the time from the first dose of study treatment until the first viral load value <50 c/mL was reached. Participants who withdrew for any reason without having suppressed prior to the analysis were censored.	From Baseline until Week 144) (average of 877.4 days for DTG; average of 788.8 study days for EFV/TDF/FTC)
Secondary	Percentage of Participants With Plasma Human Immunodeficiency Virus -1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 96 and Week 144	The percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 96 and Week 144 was assessed. Plasma samples were collected for the quantitative assessment of HIV-1 RNA based on the Missing, Switch, or Discontinuation equals Failure (MSDF) algorithm,as codified by the Food and Drug Administration's Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigationl product prior to the visit window) as non-responders, as well as participants who switched their concomitant antiretroviral therapy (ART) in certain scenarios. Since changes in ART were not permitted in this protocol, all such participants who changed ART were to be considered non-responders. Otherwise, virologic success or failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the visit of interest window.	Week 96 and Week 144
Secondary	Number of Participants With a Confirmed Plasma HIV-1 RNA Level >=1000 c/mL at or After Week 16 and Before Week 24, or a Confirmed Plasma HIV-1 RNA Level >=200 c/mL at or After Week 24	Data are presented as Kaplan Meier estimates of virologic failure (VF), defined as a confirmed plasma HIV-1 RNA level >=1000 c/mL at or after Week 16 and before Week 24, or a confirmed plasma HIV-1 RNA level >=200 c/mL at or after Week 24. A plasma HIV-1 RNA value was considered to be confirmed failure if a consecutive measurement satisfied the same failure criterion. The number of participants who experienced autoimmune deficiency syndrome (AIDS) Clinical Trials Group (ACTG) VFs was measured. For participants who withdrew from the study/were not documented to have reached confirmed VF at the cut off date of the Week 48 analysis, time to VF was to be censored at the planned visit week of the last measured plasma HIV-1 RNA sample. Data for participants who missed three consecutive scheduled plasma HIV-1 RNA measurements were to be censored at the planned visit week of the last assessment prior to the 3 consecutive missed visits.	From Baseline until Week 144) (average of 877.4 days for DTG; average of 788.8 study days for EFV/TDF/FTC)
Secondary	Change From Baseline in Plasma HIV-1 RNA at Weeks 2, 4, 8, 12, 16, 24, 32, 40,48, 60, 72, 84, 96, 108, 120, 132 and 144	Blood samples were collected for the measurement of HIV-1 RNA in plasma. Changes from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the indicated time points were assessed (represented by n=X, X in the category titles).	Baseline and at Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144
Secondary	Change From Baseline in CD4+ Cell Counts at Week 144	Cluster of differentiation (CD4) lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immunocompromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy. Change from Baseline was calculated as the Week 144 value minus the Baseline value. The least squares mean is the estimated mean change from Baseline in CD4+ cell counts at Week 144 calculated from a repeated measures model including the following covariates: treatment, visit, Baseline plasma HIV-1 RNA, Baseline CD4+ cell count, treatment*visit interaction, Baseline HIV-1 RNA*visit interaction, and Baseline CD4+ cell count*visit interaction. No assumptions were made about the correlations between a participant's readings of CD4+, i.e., the correlation matrix for within-participant errors is unstructured.	Baseline and Week 144
Secondary	Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144	CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immunocompromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy. Change from Baseline was calculated as the value at Indicated visit minus the Baseline value. Only those participants available at the indicated time points were assessed (represented by n=X, X in the category titles).	Baseline and Week 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144
Secondary	Number of Participants With the Indicated Post-baseline HIV-associated Conditions and Progression, Excluding Recurrences at Week 144	Clinical disease progression (CDP) was assessed according to the Centers for Disease Control and Prevention (CDC) HIV-1 classification system. Category (CAT) A: one or more of the following conditions (CON), without any CON listed in Categories B and C: asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition. Indicators of CDP were defined as: CDC CAT A at Baseline (BS) to a CDC CAT C event (EV); CDC CAT B at BS to a CDC CAT C EV; CDC CAT C at BS to a new CDC CAT C EV; or CDC CAT A, B, or C at BS to death.	From Baseline until Week 144
Secondary	Number of Participants With the Indicated Grade 1 to 4 Clinical and Hematology Toxicities at Week144	All Grade 1 to 4 post-Baseline-emergent chemistry toxicities included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), asparate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, low density lipoprotein (LDL) cholesterol calculation, lipase, phosphorus inorganic, total bilirubin, and triglycerides. All Grade 1 to 4 post-Baseline-emergent hematology toxities included hemoglobin, platelet count, total neutrophils, and white blood cell count. The Division of AIDS (DAIDS) defined toxicity grades as follows: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening; Grade 5, death.	From Baseline until Week 144
Secondary	Number of Participants With the Indicated Genotypic Resistance With Virological Failure (VF) Through 144	Whole blood samples were collected from participants to provide plasma for storage samples for potential viral genotypic and phenotypic analyses. Participants with confirmed virological failure (confirmed HIV-1 RNA >=50 copies/mL throughout the study and/or confirmed HIV-1 RNA >=200 copies/mL at Week 144) had plasma samples tested for HIV-1 RT genotype and HIV-1 integrase genotype from Baseline samples and from samples collected at the time of virological failure. Genotype testing was conducted at Day 1 and at the time of suspected protocol-defined virological failure (PDVF). A genotyping assessment was made of change across all amino acids within the integrase (IN)-encoding region, with particular attention paid to specific amino acid changes associated with the development of resistance to RAL, ELV, or DTG.	Through Week 144
Secondary	Change From Baseline in the Symptom Bother Score (SBS) at Week 4 Through Week 48	The Symptom Distress Module (SDM) is a 20-item, self-reported questionnaire measuring the presence/perceived distress linked to symptoms associated with HIV/its treatments. Developed with support from the AIDS Clinical Trials Group of the U.S. National Institute of Allergy and Infectious Diseases, it has demonstrated construct validity and has shown strong associations with physical/mental health summary scores and with disease severity. The SDM consists of 2 main scores: symptom count and the SBS, ranging from 0 (best) to 80 (worst) and based on the degree of bother that each symptom present posed. The SBS was calculated by adding the 20 individual bother item scores, which were calculated as: 0, "I do not have this symptom"; 1, "It doesn't bother me"; 2, "It bothers me a little"; 3, "It bothers me"; 4, "It bothers me a lot." Estimates are calculated from an analysis of covariance (ANCOVA) model adjusting for age, sex, race, Baseline (BL) viral load, BL CD4+ cell count, and BL SBS.	Baseline and Week 4 through 48