Clinical trial NCT01641809: Dose Ranging Study of GSK1265744 Plus Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus-1 (HIV-1) Virologic Suppression Followed by Virologic Suppression Maintenance by GSK1265744 Plus Rilpivirine
Official title: A Phase IIb, Dose Ranging Study of Oral GSK1265744 in Combination With Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus -1 (HIV-1) Virologic Suppression Followed by an Evaluation of Maintenance of Virologic Suppression When Oral GSK1265744 is Combined With Oral Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infection, Human Immunodeficiency Virus
HIV Infections
Keywords: HIV -1
GSK1265744
maintenance phase
dose selection
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2012-07-17
Enrollment: 244
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: The study is designed to select a dose of GSK1265744 primarily on the basis of antiviral activity and tolerability in HIV-1 infected, antiretroviral naive subjects.

This study consists of two parts:

Induction Phase: Approximately 200 subjects will be randomized (50 subjects in each of the 4 treatment arms). The Induction Phase consists of a 24 week dose-ranging evaluation of GSK1265744 at blinded doses of 10 mg, 30 mg and 60 mg once-daily and a control arm of open-label efavirenz (EFV) 600 mg once daily. The background dual nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral therapy (ART) for all arms will be either abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) as selected by the Investigator. Subjects randomized to a GSK1265744 containing arm, who successfully complete 24 weeks on study and demonstrate virologic suppression (defined as having a plasma HIV-1 ribonucleic acid \[RNA\] \<50 copies per milliliter \[c/mL\] before Week 24, with no signs of virologic rebound) will become eligible for the Maintenance Phase of this study.

Maintenance Phase: The background NRTIs will be discontinued and the subjects will continue their randomized dose of GSK1265744 in combination with rilpivirine (RPV) 25 mg once-daily for an additional 72 weeks. The Maintenance phase will evaluate the ability of this two drug ART regimen to maintain virologic suppression through Week 48, Week 72 and Week 96. Subjects randomized to the EFV arm will continue on their randomized regimen through Week 96.

After completion of the maintenance phase, subjects could enroll in the Open-Label Phase to continue GSK1265744 + RPV treatment as long as they continue to derive clinical benefit and until it is locally approved and commercially available.


Eligibility criteria: Inclusion Criteria:

* HIV-1 infected male or female subjects \>= 18 years of age
* Screening plasma HIV-1 RNA \>=1000 c/mL
* CD4+ cell count \>=200 cells/millimeter (mm)\^3
* ART-naive defined as having =\<10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection
* Female subjects of child bearing potential are eligible to enter if they are not pregnant and willing to use protocol-specified methods of contraception to prevent pregnancy during the study

Exclusion Criteria:

* Any evidence at screening of an active Centers for Disease and Prevention Control (CDC) Category C disease
* Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
* History of ongoing or clinically relevant hepatitis within the previous 6 months, and subjects with moderate to severe hepatic impairment will be excluded
* Women who are breastfeeding
* Subject, who in the investigator's judgment, poses a significant suicide risk
* Any clinically significant finding on screening or baseline electrocardiograph (ECG)
* The presence of any specific laboratory abnormalities at Screening
* History of cardiac disease
* Clinically relevant pancreatitis
* Subjects who are unlikely to complete the dosing schedule due to a pre-existing physical or mental condition
* Any condition which impairs the absorption, distribution, metabolism or excretion of the investigational product
* Any evidence of primary resistance based upon the presence of a major resistance associated mutation in the Screening HIV genotype, or any historical genotype
* Treatment with any protocol-specified excluded medication

Primary outcomes:
measure: Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/Milliliter (mL) at Week 48 Using the Missing, Switch, Discontinuation Equals Failure (MSDF) Algorithm
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the MSDF Algorithm
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
measure: Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the Observed Case Analysis
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
measure: Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using the MSDF Algorithm
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300 and 312
measure: Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using Observed Case Analysis
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324
measure: Absolute Values for Plasma Logarithm to the Base 10 (log10) HIV-1 RNA Over Time by Visit
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324
measure: Change From Baseline in Plasma log10 HIV-1 RNA Over Time by Visit
timeFrame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324
measure: Number of Participants With Post-Baseline HIV-1 Associated Conditions Progression of Disease
timeFrame: Up to Week 324
measure: Absolute Values for Cluster of Differentiation 4+ (CD4+) Cell Count During Double-blind Randomized Treatment Until Week 96
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
measure: Change From Baseline in CD4+ Cell Count Over Time by Visit
timeFrame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324
measure: Number of Participants With Treatment Emergent Phenotypic Resistance
timeFrame: Up to Week 324
measure: Number of Participants With Treatment Emergent Genotypic Mutations Associated With Development of Resistance
timeFrame: Up to Week 324
measure: Number of Participants With Adherence to Study Treatment
timeFrame: Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300 and 312
measure: Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 16 and Week 24 Using MSDF Algorithm-Induction Phase
timeFrame: Week 16 and Week 24
measure: Percentage of Participants With HIV-1 RNA <50 Copies/mL From Week 24 Through Week 96 by Visit Using MSDF Algorithm-Maintenance Phase
timeFrame: Weeks 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Maintenance Phase
timeFrame: Week 24 to Week 96
measure: Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities-Maintenance Phase
timeFrame: Week 24 to Week 96
measure: Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Maintenance Phase
timeFrame: Week 24 to Week 96
measure: Number of Participants With AEs and SAEs Over Time
timeFrame: Up to Week 324
measure: Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities Over Time
timeFrame: Up to Week 324
measure: Number of Participants With Maximum Treatment-emergent Hematology Toxicities Over Time
timeFrame: Up to Week 324
measure: Absolute Values for ALT, AST, CK During Double-blind Randomized Treatment Until Week 96
timeFrame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
measure: Absolute Values for Creatinine and Total Bilirubin During Double-blind Randomized Treatment Until Week 96
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
measure: Absolute Values for Estimated Creatinine Clearance During Double-blind Randomized Treatment Until Week 96
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 16, 20, 24, 26, 40, 48, 60 and 96
measure: Absolute Values for Hemoglobin During Double-blind Randomized Treatment Until Week 96
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
measure: Absolute Values for Platelet Count, Total Neutrophils and WBC Count During Double-blind Randomized Treatment Until Week 96
timeFrame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
measure: Change From Baseline in ALT, AST and CK Over Time by Visit
timeFrame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324
measure: Change From Baseline in Creatinine and Total Bilirubin Over Time by Visit
timeFrame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324
measure: Change From Baseline in Estimated Creatinine Clearance Over Time by Visit
timeFrame: Baseline (Day 1) and Weeks 2, 4, 8, 16, 20, 24, 26, 40, 48, 60, 96, 180, 204, 252 and 264
measure: Change From Baseline in Hemoglobin Level Over Time by Visit
timeFrame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324
measure: Change From Baseline in Total Neutrophils, Platelet Count and WBC Count Over Time by Visit
timeFrame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324
measure: Percentage of Participants Who Discontinued Investigational Product Due to Adverse Events
timeFrame: Up to Week 324
measure: Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
timeFrame: Up to Week 324
measure: Number of Participants With AEs and SAEs-Induction Phase
timeFrame: Up to Week 24
measure: Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicity-Induction Phase
timeFrame: Up to Week 24
measure: Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Induction Phase
timeFrame: Up to Week 24
measure: Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Induction Phase
timeFrame: Up to Week 24
measure: Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Maintenance Phase
timeFrame: Week 24 to Week 96
measure: Area Under the Concentration Time Curve Over the Dosing Interval (AUC[0-tau]) for GSK1265744 at Week 2
timeFrame: pre-dose, 1, 2, 3, 4, 8 and 24 hours post-dose at Week 2
measure: Maximum Observed Concentration (Cmax) for GSK1265744 at Week 2
timeFrame: pre-dose, 1, 2, 3, 4, 8 and 24 hours post-dose at Week 2
measure: Concentration at the End of a Dosing Interval (Ctau) for GSK1265744 at Week 2
timeFrame: pre-dose, 1, 2, 3, 4, 8 and 24 hours post dose at Week 2
measure: AUC(0 to Tau) for Rilpivirine
timeFrame: pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36
measure: Cmax for Rilpivirine
timeFrame: pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36
measure: Ctau for Rilpivirine
timeFrame: pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Little Rock
country: United States
facility: GSK Investigational Site
state: Arkansas
city: Bakersfield
country: United States
facility: GSK Investigational Site
state: California
city: Beverly Hills
country: United States
facility: GSK Investigational Site
state: California
city: Long Beach
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
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 Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Pierce
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Oakland Park
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: West Palm Beach
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: Macon
country: United States
facility: GSK Investigational Site
state: Georgia
city: Savannah
country: United States
facility: GSK Investigational Site
state: Georgia
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Omaha
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Hillsborough
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Neptune
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Albany
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: 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: Providence
country: United States
facility: GSK Investigational Site
state: Rhode Island
city: Charleston
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Annandale
country: United States
facility: GSK Investigational Site
state: Virginia
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
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
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Mills A, Richmond GJ, Newman C, Osiyemi O, Cade J, Brinson C, De Vente J, Margolis DA, Sutton KC, Wilches V, Hatch S, Roberts J, McCoig C, Garris C, Vandermeulen K, Spreen WR. Long-acting cabotegravir and rilpivirine for HIV-1 suppression: switch to 2-monthly dosing after 5 years of daily oral therapy. AIDS. 2022 Feb 1;36(2):195-203. doi: 10.1097/QAD.0000000000003085.
citation: Patel P, Xue Z, King KS, Parham L, Ford S, Lou Y, Bakshi KK, Sutton K, Margolis D, Hughes AR, Spreen WR. Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir. J Antimicrob Chemother. 2020 Aug 1;75(8):2240-2248. doi: 10.1093/jac/dkaa147.
citation: Margolis DA, Brinson CC, Smith GHR, de Vente J, Hagins DP, Eron JJ, Griffith SK, Clair MHS, Stevens MC, Williams PE, Ford SL, Stancil BS, Bomar MM, Hudson KJ, Smith KY, Spreen WR; LAI116482 Study Team. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015 Oct;15(10):1145-1155. doi: 10.1016/S1473-3099(15)00152-8. Epub 2015 Jul 19.