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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Infection, Human Immunodeficiency Virus
• Intervention / Treatment: Drug: GSK1265744 10 mg; Drug: Rilpivirine 25 mg; Drug: Placebo; Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC); Drug: GSK1265744 30 mg; Drug: GSK1265744 60 mg; Drug: Efavirenz 600 mg

• Study Type: Interventional
• Enrollment (Actual): 244
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2T1
      • GSK Investigational Site
    • Vancouver, British Columbia, Canada, V6Z 2C7
      • GSK Investigational Site
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • GSK Investigational Site
    • Toronto, Ontario, Canada, M5G 1K2
      • GSK Investigational Site
    • Toronto, Ontario, Canada, M4T 3A7
      • GSK Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H2L 4E9
      • GSK Investigational Site
    • Montreal, Quebec, Canada, H3A 1T1
      • GSK Investigational Site
    • Montreal, Quebec, Canada, H2L 4P9
      • GSK Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • GSK Investigational Site
  • Arizona
    • Phoenix, Arizona, United States, 85015
      • GSK Investigational Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72207
      • GSK Investigational Site
  • California
    • Bakersfield, California, United States, 93301
      • GSK Investigational Site
    • Beverly Hills, California, United States, 90211
      • GSK Investigational Site
    • Long Beach, California, United States, 90813
      • GSK Investigational Site
    • Los Angeles, California, United States, 90069
      • GSK Investigational Site
    • San Francisco, California, United States, 94115
      • GSK Investigational Site
  • Colorado
    • Denver, Colorado, United States, 80209
      • GSK Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • GSK Investigational Site
    • Washington, District of Columbia, United States, 20037
      • GSK Investigational Site
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • GSK Investigational Site
    • Fort Lauderdale, Florida, United States, 33308
      • GSK Investigational Site
    • Fort Pierce, Florida, United States, 34982
      • GSK Investigational Site
    • Miami, Florida, United States, 33137
      • GSK Investigational Site
    • Oakland Park, Florida, United States, 33309
      • GSK Investigational Site
    • Orlando, Florida, United States, 32803
      • GSK Investigational Site
    • West Palm Beach, Florida, United States, 33407
      • GSK Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30339
      • GSK Investigational Site
    • Augusta, Georgia, United States, 30912
      • GSK Investigational Site
    • Macon, Georgia, United States, 31201
      • GSK Investigational Site
    • Savannah, Georgia, United States, 31401
      • GSK Investigational Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • GSK Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • GSK Investigational Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • GSK Investigational Site
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • GSK Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • GSK Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • GSK Investigational Site
  • New Jersey
    • Hillsborough, New Jersey, United States, 08844
      • GSK Investigational Site
    • Neptune, New Jersey, United States, 07753
      • GSK Investigational Site
  • New York
    • Albany, New York, United States, 12209
      • GSK Investigational Site
    • Buffalo, New York, United States, 14201
      • GSK Investigational Site
    • New York, New York, United States, 10065
      • GSK Investigational Site
    • Valhalla, New York, United States, 10595
      • GSK Investigational Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • GSK Investigational Site
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • GSK Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • GSK Investigational Site
  • Texas
    • Austin, Texas, United States, 78751
      • GSK Investigational Site
    • Dallas, Texas, United States, 75246
      • GSK Investigational Site
  • Virginia
    • Annandale, Virginia, United States, 22003
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 GSK1265744 10 mg; In the Induction Phase subjects will receive oral tablets of GSK1265744 10 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 10 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.	Drug: GSK1265744 10 mg; GSK1265744 10 mg will be administered orally once daily in combination with investigator-selected background NRTIs in the Induction Phase of the study and in combination with Rilpivirine 25 mg in the Maintenance Phase of the study.; Drug: Rilpivirine 25 mg; Rilpivirine 25 mg will be administered orally once daily in combination with GSK1265744 10 mg, 30 mg and 60 mg in the Maintenance Phase of the study.; Drug: Placebo; Placebo matching to GSK1265744 will be administered along with GSK1265744 10 mg and 30 mg in the Induction phase and Maintenance phase of the study.; Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC); The background dual NRTI therapy for all arms in the Induction Phase and Efavirenz 600 mg arm in the Maintenance Phase will be either abacavir 600 mg + lamivudine 300 mg (ABC/3TC) or tenofovir 300 mg + emtricitabine 200 mg (TDF/FTC) as selected by the Investigator.
Experimental: Arm 2 GSK1265744 30 mg; In the Induction Phase subjects will receive oral tablets of GSK1265744 30 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 30 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.	Drug: Rilpivirine 25 mg; Rilpivirine 25 mg will be administered orally once daily in combination with GSK1265744 10 mg, 30 mg and 60 mg in the Maintenance Phase of the study.; Drug: Placebo; Placebo matching to GSK1265744 will be administered along with GSK1265744 10 mg and 30 mg in the Induction phase and Maintenance phase of the study.; Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC); The background dual NRTI therapy for all arms in the Induction Phase and Efavirenz 600 mg arm in the Maintenance Phase will be either abacavir 600 mg + lamivudine 300 mg (ABC/3TC) or tenofovir 300 mg + emtricitabine 200 mg (TDF/FTC) as selected by the Investigator.; Drug: GSK1265744 30 mg; GSK1265744 30 mg will be administered orally once daily in combination with investigator-selected background NRTIs in the Induction Phase of the study and in combination with Rilpivirine 25 mg in the Maintenance Phase of the study.
Experimental: Arm 3 GSK1265744 60 mg; In the Induction Phase subjects will receive oral tablets of GSK1265744 60 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 60 mg + Rilpivirine 25 mg once daily from Week 24 to Week 96.	Drug: Rilpivirine 25 mg; Rilpivirine 25 mg will be administered orally once daily in combination with GSK1265744 10 mg, 30 mg and 60 mg in the Maintenance Phase of the study.; Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC); The background dual NRTI therapy for all arms in the Induction Phase and Efavirenz 600 mg arm in the Maintenance Phase will be either abacavir 600 mg + lamivudine 300 mg (ABC/3TC) or tenofovir 300 mg + emtricitabine 200 mg (TDF/FTC) as selected by the Investigator.; Drug: GSK1265744 60 mg; GSK1265744 60 mg will be administered orally once daily in combination with investigator-selected background NRTIs in the Induction Phase of the study and in combination with Rilpivirine 25 mg in the Maintenance Phase of the study.
Active Comparator: Arm 4 Efavirenz 600 mg; In the Induction Phase and Maintenance Phase subjects will receive oral tablets of Efavirenz 600 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine).	Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC); The background dual NRTI therapy for all arms in the Induction Phase and Efavirenz 600 mg arm in the Maintenance Phase will be either abacavir 600 mg + lamivudine 300 mg (ABC/3TC) or tenofovir 300 mg + emtricitabine 200 mg (TDF/FTC) as selected by the Investigator.; Drug: Efavirenz 600 mg; Efavirenz 600 mg will be administered orally once daily in combination with investigator-selected background NRTIs in the Induction Phase and Maintenance Phase of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Plasma samples were collected for quantitative analysis of HIV-1 RNA. Percentage of participants with HIV-1 RNA <50 copies/mL at Week 48 was determined using the MSDF algorithm based on the current US Food and Drug Administration (FDA) definition of Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to visit window) as well as participants who switch their concomitant antiretroviral therapy prior to the visit of interest as non-responders. Virological response within an analysis window was determined by the last available HIV-1 RNA measurement in that window while the participant was on-treatment. MSDF response rate was calculated as number of responders in the analysis window divided by the number of participants in the analysis population. ITT-E Population comprised of all randomized participants who received at least one dose of investigational product.	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the MSDF Algorithm	Plasma samples were collected for quantitative analysis of HIV-1 RNA. The percentage of participants with HIV-1 RNA <400 copies/mL over time was determined using the MSDF algorithm based on the current US FDA definition of the Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to visit window) as well as participants who switch their concomitant antiretroviral therapy prior to the visit of interest as non-responders. Virological response within an analysis window was determined by the last available HIV-1 RNA measurement in that window while the participant was on-treatment. MSDF response rate was calculated as number of responders in the analysis window divided by the number of participants in the analysis population.	Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the Observed Case Analysis	Plasma samples were collected for quantitative analysis of HIV-1 RNA. Percentage of participants with HIV-1 RNA <400 copies/mL over time was determined using the observed case analysis, which did not impute for any missing assessments. Observed case response rate was calculated as the number of participants with a positive response at the time point where the participant is on randomized therapy divided by the number of participants in the analysis population with an assessment in the scheduled visit window during the randomized period.	Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using the MSDF Algorithm	Plasma samples were collected for quantitative analysis of HIV-1 RNA. Percentage of participants with HIV-1 RNA <50 copies/mL over time was determined using the MSDF algorithm based on the current US FDA definition of the Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to visit window) as well as participants who switch their concomitant antiretroviral therapy prior to the visit of interest as non-responders. Virological response within an analysis window was determined by the last available HIV-1 RNA measurement in that window while the participant was on-treatment. MSDF response rate was calculated as number of responders in the analysis window divided by the number of participants in the analysis population.	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
Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using Observed Case Analysis	Plasma samples were collected for quantitative analysis of HIV-1 RNA. Percentage of participants with HIV-1 RNA <50 copies/mL over time was determined using the observed case analysis, which did not impute for any missing assessments. Observed case response rate was calculated as the number of participants with a positive response at the time point where the participant is on therapy divided by the number of participants in the analysis population with an assessment in the scheduled visit window during the randomized period or open-label phase.	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
Absolute Values for Plasma Logarithm to the Base 10 (log10) HIV-1 RNA Over Time by Visit	Plasma samples for quantitative analysis of HIV-1 RNA were collected at indicated time points. Baseline value is the last pre-treatment value observed.	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
Change From Baseline in Plasma log10 HIV-1 RNA Over Time by Visit	Plasma samples for quantitative analysis of HIV-1 RNA were collected at indicated time points. Baseline value is the last pre-treatment value observed. Change from Baseline is calculated as value at indicated time point minus Baseline value.	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
Number of Participants With Post-Baseline HIV-1 Associated Conditions Progression of Disease	HIV-1 associated conditions were assessed according to the 1993 Centers for Disease Control and Prevention (CDC) Revised Classification System for HIV Infection in Adults. The clinical categories of HIV infection as per CDC system are class A=Asymptomatic HIV infection or lymphadenopathy or acute HIV infection; class B=symptomatic non-acquired immunodeficiency syndrome (AIDS) conditions and class C=AIDS indicator conditions. Number of participants experiencing disease progression is presented, where disease progression is defined as the progression from Baseline HIV disease status as follows: CDC class A at Baseline to CDC class C event; CDC Class B at Baseline to CDC Class C event; CDC Class C at Baseline to new CDC Class C event; and CDC class A, B or C at Baseline to death.	Up to Week 324
Absolute Values for Cluster of Differentiation 4+ (CD4+) Cell Count During Double-blind Randomized Treatment Until Week 96	CD4+ cell counts were assessed by flow cytometry. Baseline value is the last pre-treatment value observed.	Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
Change From Baseline in CD4+ Cell Count Over Time by Visit	CD4+ cell counts were assessed by flow cytometry. Baseline value is the last pre-treatment value observed. Change from Baseline is calculated as value at indicated time point minus Baseline value.	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
Number of Participants With Treatment Emergent Phenotypic Resistance	Plasma samples were collected for drug resistance testing. Phenotypic resistance data for the following drugs under integrase inhibitor (INI), non-nucleoside reverse transcriptase inhibitor (NNRTI), NRTI and proteasome inhibitor drug classes is presented for participants with confirmed virologic failure: GSK1265744, Raltegravir [RAL], Delavirdine [DLV], Efavirenz [EFV], Etravirine [ETR], Nevirapine (NVP), RPV, 3TC, ABC, FTC, TDF, Zidovudine [ZDV], Stavudine [d4T], Didanosine [ddI], Atazanavir/ritonavir [ATV/r], Darunavir (DRV)/r, Fosamprenavir/r [FPV/r], Indinavir/r [IDV/r], Lopinavir/r [LPV/r], Nelfinavir [NFV], Ritonavir [RTV], Saquinavir/r [SQV/r], Tipranavir/r [TPV/r]. On-treatment Phenotypic Resistance population comprised of all participants in the ITT-E Population with available on-treatment phenotypic resistance data, excluding participants who are not protocol-defined virologic failures.	Up to Week 324
Number of Participants With Treatment Emergent Genotypic Mutations Associated With Development of Resistance	Plasma samples were collected for drug resistance testing. The treatment emergent INI mutations associated with development of resistance to RAL, ELV, dolutegravir (DTG) or GSK1265744 and major resistance mutations to other classes (NRTI, NNRTI, PI) as defined by International AIDS society (IAS)-United States of America (USA) are presented. On-treatment Genotypic Resistance population comprised of all participants in the ITT-E Population with available on-treatment genotypic resistance data, excluding participants who are not protocol-defined virologic failures.	Up to Week 324
Number of Participants With Adherence to Study Treatment	Number of participants with >=90% adherence to study treatment based on pill count is summarized.	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
Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 16 and Week 24 Using MSDF Algorithm-Induction Phase	Plasma samples were collected for quantitative analysis of HIV-1 RNA. Percentage of participants with HIV-1 RNA <50 copies/mL over time was determined using the MSDF algorithm based on the current US FDA definition of the Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to visit window) as well as participants who switch their concomitant antiretroviral therapy prior to the visit of interest as non-responders. Virological response within an analysis window was determined by the last available HIV-1 RNA measurement in that window while the participant was on-treatment. MSDF response rate was calculated as number of responders in the analysis window divided by the number of participants in the analysis population.	Week 16 and Week 24
Percentage of Participants With HIV-1 RNA <50 Copies/mL From Week 24 Through Week 96 by Visit Using MSDF Algorithm-Maintenance Phase	Plasma samples were collected for quantitative analysis of HIV-1 RNA. The end point was determined using MSDF algorithm based on the current US FDA definition of Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to visit window) as well as participants who switch their concomitant antiretroviral therapy prior to the visit of interest as non-responders. Virological response within an analysis window was determined by the last available HIV-1 RNA measurement in that window while the participant was on-treatment. MSDF response rate was calculated as number of responders in the analysis window divided by the number of participants in the analysis population. ITT-Maintenance Exposed (ME) Population comprised of all participants randomized to GSK1265744 and who received at least one dose of investigational product during maintenance phase of the study.	Weeks 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Maintenance Phase	An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; other medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the outcomes mentioned before; all events of possible drug-induced liver injury with hyperbilirubinemia. Maintenance Safety Population comprised of all participants randomized to GSK1265744 and who were exposed to investigational products during the maintenance phase of the study with the exception of any participants with documented evidence of not having consumed any amount of investigational product.	Week 24 to Week 96
Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities-Maintenance Phase	Blood samples were collected for the analysis of following clinical chemistry parameters: alanine aminotranferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), carbon dioxide(CO2)/bicarbonate, cholesterol, creatine kinase (CK), creatinine, glucose, low density lipoprotein (LDL) cholesterol, lipase, inorganic phosphorus, potassium, sodium, total bilirubin and triglycerides. A toxicity is considered treatment emergent if it developed or increased in intensity from Baseline while on-treatment. Laboratory toxicities were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, where Grade 1=Mild, Grade 2=moderate, Grade 3=severe and Grade 4=potentially life-threatening.	Week 24 to Week 96
Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Maintenance Phase	Blood samples were collected for the analysis of following hematology parameters: Activated Partial Thromboplastin Time (APTT), hemoglobin, international normalized ratio (INR), platelet count, prothrombin time (PT), total neutrophils and white blood cell (WBC) count. A toxicity is considered treatment emergent if it developed or increased in intensity from Baseline while on-treatment. Laboratory toxicities were graded using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, where Grade 1=Mild, Grade 2=moderate, Grade 3=severe and Grade 4=potentially life-threatening.	Week 24 to Week 96
Number of Participants With AEs and SAEs Over Time	An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; other medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the outcomes mentioned before; all events of possible drug-induced liver injury with hyperbilirubinemia. Safety Population comprised of all randomized participants who were exposed to investigational products with the exception of any participants with documented evidence of not having consumed any amount of investigational product.	Up to Week 324
Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities Over Time	Blood samples were collected for the analysis of following clinical chemistry parameters: ALT, albumin, ALP, AST, CO2/bicarbonate, cholesterol, CK, creatinine, glucose, LDL cholesterol, lipase, inorganic phosphorus, potassium, sodium, total bilirubin and triglycerides. Laboratory toxicities were graded using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, where Grade 1=Mild, Grade 2=moderate, Grade 3=severe and Grade 4=potentially life-threatening.	Up to Week 324
Number of Participants With Maximum Treatment-emergent Hematology Toxicities Over Time	Blood samples were collected for the analysis of following hematology parameters: APTT, hemoglobin, INR, platelet count, PT, total neutrophils and WBC count. Laboratory toxicities were graded using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, where Grade 1=Mild, Grade 2=moderate, Grade 3=severe and Grade 4=potentially life-threatening.	Up to Week 324
Absolute Values for ALT, AST, CK During Double-blind Randomized Treatment Until Week 96	Blood samples were collected for the analysis of ALT, AST and CK. Baseline value is the last pre-treatment value observed.	Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
Absolute Values for Creatinine and Total Bilirubin During Double-blind Randomized Treatment Until Week 96	Blood samples were collected for the analysis of creatinine and total bilirubin (T. bilirubin). Baseline value is the last pre-treatment value observed.	Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
Absolute Values for Estimated Creatinine Clearance During Double-blind Randomized Treatment Until Week 96	Blood samples were collected for the analysis of estimated creatinine clearance. Estimated creatinine clearance was calculated using Cockcroft-Gault formula. Baseline value is the last pre-treatment value observed.	Baseline (Day 1), Weeks 2, 4, 8, 16, 20, 24, 26, 40, 48, 60 and 96
Absolute Values for Hemoglobin During Double-blind Randomized Treatment Until Week 96	Blood samples were collected for the analysis of hemoglobin level. Baseline value is the last pre-treatment value observed.	Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
Absolute Values for Platelet Count, Total Neutrophils and WBC Count During Double-blind Randomized Treatment Until Week 96	Blood samples were collected for the analysis of platelet count, total neutrophils (T. neutrophils) and WBC count. Baseline value is the last pre-treatment value observed.	Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96
Change From Baseline in ALT, AST and CK Over Time by Visit	Blood samples were collected for the analysis of ALT, AST and CK. Baseline value is the last pre-treatment value observed. Change from Baseline is calculated as value at indicated time point minus Baseline value.	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
Change From Baseline in Creatinine and Total Bilirubin Over Time by Visit	Blood samples were collected for the analysis of creatinine and total bilirubin. Baseline value is the last pre-treatment value observed. Change from Baseline is calculated as value at indicated time point minus Baseline value.	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
Change From Baseline in Estimated Creatinine Clearance Over Time by Visit	Blood samples were collected for the analysis of estimated creatinine clearance. Estimated creatinine clearance was calculated using Cockcroft-Gault formula. Baseline value is the last pre-treatment value observed. Change from Baseline is calculated as value at indicated time point minus Baseline value.	Baseline (Day 1) and Weeks 2, 4, 8, 16, 20, 24, 26, 40, 48, 60, 96, 180, 204, 252 and 264
Change From Baseline in Hemoglobin Level Over Time by Visit	Blood samples were collected for the analysis of hemoglobin level. Baseline value is the last pre-treatment value observed. Change from Baseline is calculated as value at indicated time point minus Baseline value.	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
Change From Baseline in Total Neutrophils, Platelet Count and WBC Count Over Time by Visit	Blood samples were collected for the analysis of total neutrophils, platelet count and WBC count. Baseline value is the last pre-treatment value observed. Change from Baseline is calculated as value at indicated time point minus Baseline value.	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
Percentage of Participants Who Discontinued Investigational Product Due to Adverse Events	AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants with adverse events leading to withdrawal/permanent discontinuation of investigational product is presented.	Up to Week 324
Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings	Twelve lead ECG was performed after the participants had rested in a semi-supine position for at least 5 minutes using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for worst case results at any time on-treatment is presented.	Up to Week 324
Number of Participants With AEs and SAEs-Induction Phase	An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; other medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the outcomes mentioned before; all events of possible drug-induced liver injury with hyperbilirubinemia.	Up to Week 24
Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicity-Induction Phase	Blood samples were collected for the analysis of following clinical chemistry parameters: ALT, albumin, ALP, AST, CO2/bicarbonate, chloride, cholesterol, CK, creatinine, glucose, high density lipoprotein (HDL) cholesterol, LDL cholesterol, lipase, inorganic phosphorus, potassium, sodium, total bilirubin, triglycerides and urea/blood urea nitrogen (BUN). A toxicity was considered treatment emergent if it developed or increased in intensity from Baseline while on-treatment. Laboratory toxicities were graded using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, where Grade 1=Mild, Grade 2=moderate, Grade 3=severe and Grade 4=potentially life-threatening.	Up to Week 24
Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Induction Phase	Blood samples were collected for the analysis of following hematology parameters: APTT, basophils, eosinophils, hematocrit, hemoglobin, INR, lymphocytes, mean corpuscle volume (MCV), monocytes, platelet count, PT, red blood cell (RBC) count, total neutrophils and WBC count. A toxicity was considered treatment emergent if it developed or increased in intensity from Baseline while on-treatment. Laboratory toxicities were graded using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, where Grade 1=Mild, Grade 2=moderate, Grade 3=severe and Grade 4=potentially life-threatening.	Up to Week 24
Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Induction Phase	AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants with adverse events leading to withdrawal/permanent discontinuation of investigational product is presented.	Up to Week 24
Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Maintenance Phase	AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants with adverse events leading to withdrawal/permanent discontinuation of investigational product is presented.	Week 24 to Week 96
Area Under the Concentration Time Curve Over the Dosing Interval (AUC[0-tau]) for GSK1265744 at Week 2	Blood samples for pharmacokinetic (PK) analysis were collected at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. The PK Summary Population comprised of all participants who received GSK1265744 or with Rilpivirine, underwent intensive and/or limited/sparse PK sampling during the study, and provided evaluable GSK1265744 and Rilpivirine plasma concentration data	pre-dose, 1, 2, 3, 4, 8 and 24 hours post-dose at Week 2
Maximum Observed Concentration (Cmax) for GSK1265744 at Week 2	Blood samples for PK analysis were collected at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.	pre-dose, 1, 2, 3, 4, 8 and 24 hours post-dose at Week 2
Concentration at the End of a Dosing Interval (Ctau) for GSK1265744 at Week 2	Blood samples for PK analysis were collected at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.	pre-dose, 1, 2, 3, 4, 8 and 24 hours post dose at Week 2
AUC(0 to Tau) for Rilpivirine	Data was not collected for analysis of rilpivirine PK parameters.	pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36
Cmax for Rilpivirine	Data was not collected for analysis of rilpivirine PK parameters.	pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36
Ctau for Rilpivirine	Data was not collected for analysis of rilpivirine PK parameters.	pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Collaborators: GlaxoSmithKline

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2012
• Primary Completion (Actual): October 10, 2013
• Study Completion (Actual): January 15, 2019

Study Registration Dates

• First Submitted: June 28, 2012
• First Submitted That Met QC Criteria: July 12, 2012
• First Posted (Estimate): July 17, 2012

Study Record Updates

• Last Update Posted (Actual): January 30, 2020
• Last Update Submitted That Met QC Criteria: January 21, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: HIV -1; GSK1265744; maintenance phase; dose selection
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Integrase Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Emtricitabine; Lamivudine; Efavirenz; Rilpivirine; Abacavir; Cabotegravir
• Other Study ID Numbers: 116482