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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

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ClinicalTrials.gov Identifier: NCT01641809
Recruitment Status : Completed
First Posted : July 17, 2012
Results First Posted : January 30, 2020
Last Update Posted : January 30, 2020
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare

Tracking Information
First Submitted Date  ICMJE June 28, 2012
First Posted Date  ICMJE July 17, 2012
Results First Submitted Date  ICMJE January 21, 2020
Results First Posted Date  ICMJE January 30, 2020
Last Update Posted Date January 30, 2020
Actual Study Start Date  ICMJE August 6, 2012
Actual Primary Completion Date October 10, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 21, 2020)
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 [ Time Frame: Week 48 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 12, 2012)
Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 [ Time Frame: 48 weeks ]
Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 will be based on Intent-to-Treat Exposed (ITT-E) Population (all randomized subjects who received at least one dose of study drug) using the missing, switch, or discontinuation equals failure (MSDF) algorithm.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 21, 2020)
  • Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the MSDF Algorithm [ Time Frame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96 ]
    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.
  • Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the Observed Case Analysis [ Time Frame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96 ]
    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.
  • Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using the MSDF Algorithm [ Time Frame: 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 ]
    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.
  • Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using Observed Case Analysis [ Time Frame: 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 ]
    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.
  • Absolute Values for Plasma Logarithm to the Base 10 (log10) HIV-1 RNA Over Time by Visit [ Time Frame: 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 ]
    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 in Plasma log10 HIV-1 RNA Over Time by Visit [ Time Frame: 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 ]
    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.
  • Number of Participants With Post-Baseline HIV-1 Associated Conditions Progression of Disease [ Time Frame: Up to Week 324 ]
    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.
  • Absolute Values for Cluster of Differentiation 4+ (CD4+) Cell Count During Double-blind Randomized Treatment Until Week 96 [ Time Frame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96 ]
    CD4+ cell counts were assessed by flow cytometry. Baseline value is the last pre-treatment value observed.
  • Change From Baseline in CD4+ Cell Count Over Time by Visit [ Time Frame: 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 ]
    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.
  • Number of Participants With Treatment Emergent Phenotypic Resistance [ Time Frame: Up to Week 324 ]
    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.
  • Number of Participants With Treatment Emergent Genotypic Mutations Associated With Development of Resistance [ Time Frame: Up to Week 324 ]
    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.
  • Number of Participants With Adherence to Study Treatment [ Time Frame: 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 ]
    Number of participants with >=90% adherence to study treatment based on pill count is summarized.
  • Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 16 and Week 24 Using MSDF Algorithm-Induction Phase [ Time Frame: Week 16 and Week 24 ]
    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.
  • Percentage of Participants With HIV-1 RNA <50 Copies/mL From Week 24 Through Week 96 by Visit Using MSDF Algorithm-Maintenance Phase [ Time Frame: Weeks 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96 ]
    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.
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Maintenance Phase [ Time Frame: Week 24 to Week 96 ]
    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.
  • Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities-Maintenance Phase [ Time Frame: Week 24 to Week 96 ]
    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.
  • Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Maintenance Phase [ Time Frame: Week 24 to Week 96 ]
    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.
  • Number of Participants With AEs and SAEs Over Time [ Time Frame: Up to Week 324 ]
    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.
  • Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities Over Time [ Time Frame: Up to Week 324 ]
    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.
  • Number of Participants With Maximum Treatment-emergent Hematology Toxicities Over Time [ Time Frame: Up to Week 324 ]
    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.
  • Absolute Values for ALT, AST, CK During Double-blind Randomized Treatment Until Week 96 [ Time Frame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96 ]
    Blood samples were collected for the analysis of ALT, AST and CK. Baseline value is the last pre-treatment value observed.
  • Absolute Values for Creatinine and Total Bilirubin During Double-blind Randomized Treatment Until Week 96 [ Time Frame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96 ]
    Blood samples were collected for the analysis of creatinine and total bilirubin (T. bilirubin). Baseline value is the last pre-treatment value observed.
  • Absolute Values for Estimated Creatinine Clearance During Double-blind Randomized Treatment Until Week 96 [ Time Frame: Baseline (Day 1), Weeks 2, 4, 8, 16, 20, 24, 26, 40, 48, 60 and 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.
  • Absolute Values for Hemoglobin During Double-blind Randomized Treatment Until Week 96 [ Time Frame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96 ]
    Blood samples were collected for the analysis of hemoglobin level. Baseline value is the last pre-treatment value observed.
  • Absolute Values for Platelet Count, Total Neutrophils and WBC Count During Double-blind Randomized Treatment Until Week 96 [ Time Frame: Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 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.
  • Change From Baseline in ALT, AST and CK Over Time by Visit [ Time Frame: 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 ]
    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.
  • Change From Baseline in Creatinine and Total Bilirubin Over Time by Visit [ Time Frame: 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 ]
    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.
  • Change From Baseline in Estimated Creatinine Clearance Over Time by Visit [ Time Frame: Baseline (Day 1) and Weeks 2, 4, 8, 16, 20, 24, 26, 40, 48, 60, 96, 180, 204, 252 and 264 ]
    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.
  • Change From Baseline in Hemoglobin Level Over Time by Visit [ Time Frame: 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 ]
    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.
  • Change From Baseline in Total Neutrophils, Platelet Count and WBC Count Over Time by Visit [ Time Frame: 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 ]
    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.
  • Percentage of Participants Who Discontinued Investigational Product Due to Adverse Events [ Time Frame: Up to Week 324 ]
    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.
  • Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings [ Time Frame: Up to Week 324 ]
    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.
  • Number of Participants With AEs and SAEs-Induction Phase [ Time Frame: Up to Week 24 ]
    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.
  • Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicity-Induction Phase [ Time Frame: Up to Week 24 ]
    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.
  • Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Induction Phase [ Time Frame: Up to Week 24 ]
    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.
  • Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Induction Phase [ Time Frame: Up to Week 24 ]
    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.
  • Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Maintenance Phase [ Time Frame: Week 24 to Week 96 ]
    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.
  • Area Under the Concentration Time Curve Over the Dosing Interval (AUC[0-tau]) for GSK1265744 at Week 2 [ Time Frame: pre-dose, 1, 2, 3, 4, 8 and 24 hours post-dose 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
  • Maximum Observed Concentration (Cmax) for GSK1265744 at Week 2 [ Time Frame: pre-dose, 1, 2, 3, 4, 8 and 24 hours post-dose 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.
  • Concentration at the End of a Dosing Interval (Ctau) for GSK1265744 at Week 2 [ Time Frame: pre-dose, 1, 2, 3, 4, 8 and 24 hours post dose 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.
  • AUC(0 to Tau) for Rilpivirine [ Time Frame: pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36 ]
    Data was not collected for analysis of rilpivirine PK parameters.
  • Cmax for Rilpivirine [ Time Frame: pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36 ]
    Data was not collected for analysis of rilpivirine PK parameters.
  • Ctau for Rilpivirine [ Time Frame: pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36 ]
    Data was not collected for analysis of rilpivirine PK parameters.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 12, 2012)
  • Proportion of subjects with plasma HIV-1 RNA <400 and <50 copies/mL over time by visit [ Time Frame: Through Week 96 ]
    Proportion of subjects with plasma HIV-1 RNA <400 and <50 copies/mL over time by visit will be calculated using the MSDF and observed algorithm.
  • Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 16 and Week 24 in Induction Phase [ Time Frame: 16 weeks, 24 weeks ]
    Proportion of with HIV-1 RNA <50 copies/mL at Week 16 and Week 24 in Induction Phase were based on ITT-E Population and MSDF algorithm.
  • The proportion of subjects with HIV-1 RNA <50 copies/mL from Week 24 through Week 96 by visit in Maintenance Phase [ Time Frame: 24 weeks through Week 96 ]
    The proportion of subjects with HIV-1 RNA <50 copies/mL from Week 24 through Week 96 will be determined by visit for the Intent-to-Treat Maintenance Exposed (ITT-ME) Population (all randomized subjects who received at least one dose of investigational product [IP] during the Maintenance Phase of the study) using MSDF algorithm.
  • Absolute values and change from Baseline in plasma HIV-1 RNA by visit [ Time Frame: Baseline (Study Day 1), and up to Week 96 ]
    Plasma for quantitative HIV-1 RNA will be collected at every visit from baseline till Follow-up. Methods to determine absolute plasma HIV-1 RNA were to include but not limited to the Abbott RealTime HIV-1 Assay lower limit of detection (LLOD) 40 c/mL. Change from Baseline will be calculated as post-Baseline value minus the Baseline value.
  • Incidence of disease progression [ Time Frame: Up to Week 96 ]
    Disease progression includes HIV-associated conditions, acquired immunodeficiency syndrome (AIDS) and death. HIV-associated conditions will be assessed according to the 1993 Centers for disease control and prevention (CDC) Revised Classification System for HIV Infection in Adults.
  • Absolute values and changes from baseline in CD4+ cell counts by visit [ Time Frame: Baseline (Study Day 1), and up to Week 96 ]
    Lymphocyte subsets (including CD4+) will be collected for assessment by flow cytometry.
  • Incidence of treatment emergent genotypic and phenotypic resistance to GSK1265744, RPV and other on-study ART for protocol-defined virologic failures [ Time Frame: Up to Week 96 ]
    Development of viral resistance to GSK1265744 and other on-study ART in subjects experiencing virologic failure through Week 24; and viral resistance to GSK1265744 and rilpivirine in subjects experiencing virologic failure from Week 24 through Week 96 will be evaluated. Genotypic and phenotypic analyses may be carried out using, but not limited to, Standard Phenosense and GenoSure testing methods for protease (PRO) and reverse transcriptase (RT), or with GeneSeq Integrase and PhenoSense Integrase assays.
  • Incidence and severity of Adverse Events (AEs) and laboratory abnormalities over time [ Time Frame: Up to Week 96 ]
    The incidence and severity of AEs and laboratory abnormalities will be determined throughout the study for the Safety Population (all randomized subjects who will be exposed to IP). AEs should be graded according to the Division of AIDS (DAIDS) toxicity scales. AEs and laboratory abnormalities will also be summarized separately for Induction Phase; and Maintenance Phase using the Maintenance Safety Population (all randomized subjects who will be exposed to IP during the Maintenance Phase of the study).
  • Absolute values and changes in laboratory parameters by visit [ Time Frame: Up to Week 96 ]
    Monitoring of hematology, blood chemistry and fasting lipids will be done and changes by visit will be summarized.
  • Proportion of subjects who discontinue treatment due to AEs [ Time Frame: Up to Week 96 ]
    Proportion of subjects who discontinue treatment due to AEs will be determined throughout the study for the Safety Population; subjects who discontinue treatment due to AEs through Week 24 will be also determined in the Induction Phase; and subjects who discontinue treatment due to AEs from Week 24 through Week 96, will be determined using the Maintenance Safety Population.
  • Incidence of any clinically significant changes in QRS duration, QTc interval, HR, PR interval based on electrocardiograph (ECG) readings by visit [ Time Frame: Baseline (Study Day 1), and up to Week 96 ]
    ECGs will be performed in triplicate at least 5 minutes apart and following 5 minutes of rest in a semi-supine position within 1 hour prior to first dose. Subsequent ECG evaluations during the study should be obtained 2 to 4 hours after GSK1265744 dose.
  • Plasma GSK1265744 pharmacokinetic (PK) parameters [area under the concentration time curve over the dosing interval (AUC[0-tau]), maximum observed concentration (Cmax), and concentration at the end of a dosing interval (Ctau)] [ Time Frame: 2 weeks, 12 weeks, 26 weeks, and 36 weeks (Pre-dose and 2 to 4 hours (h) post dose) ]
    The Plasma GSK1265744 PK parameters will be estimated by non-compartmental analysis and/or population PK. The PK data collected in this study will be included in the analysis to investigate the exposure-response relationship and the integrated drug-viral dynamic modeling which will ultimately be used in guiding dose selection.
  • Plasma rilpivirine PK parameters [AUC(0-tau), Cmax, Ctau] [ Time Frame: 2 weeks, 12 weeks, 26 weeks, and 36 weeks (Pre-dose and 2 to 4 hours (h) post dose) ]
    The Plasma rilpivirine PK parameters will be estimated by non-compartmental analysis and/or population PK.
  • Adherence to IP [ Time Frame: Up to Week 96 ]
    Medication adherence to IP will be based on pill counts by visit.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Infection, Human Immunodeficiency Virus
  • HIV Infections
Intervention  ICMJE
  • 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: 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.
  • 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.
  • 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.
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: GSK1265744 10 mg
    • Drug: Rilpivirine 25 mg
    • Drug: Placebo
    • Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
  • 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.
    Interventions:
    • Drug: GSK1265744 30 mg
    • Drug: Rilpivirine 25 mg
    • Drug: Placebo
    • Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
  • 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.
    Interventions:
    • Drug: GSK1265744 60 mg
    • Drug: Rilpivirine 25 mg
    • Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
  • 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).
    Interventions:
    • Drug: Efavirenz 600 mg
    • Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 13, 2014)
244
Original Estimated Enrollment  ICMJE
 (submitted: July 12, 2012)
200
Actual Study Completion Date  ICMJE January 15, 2019
Actual Primary Completion Date October 10, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01641809
Other Study ID Numbers  ICMJE 116482
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party ViiV Healthcare
Study Sponsor  ICMJE ViiV Healthcare
Collaborators  ICMJE GlaxoSmithKline
Investigators  ICMJE
Study Director: GSK Clinical Trials ViiV Healthcare
PRS Account ViiV Healthcare
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP