Phase 2
Completed N=243
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
Infection, Human Immunodeficiency Virus · HIV
Source: ClinicalTrials.gov NCT01641809 ↗
Enrolled (actual)
243
Serious AEs
7.2%
Results posted
Jan 2020
Primary outcomePrimary: 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 — 80; 80; 87; 71 Percentage of participants
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 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 |
80; 80; 87; 71 | — |
| SECONDARY Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the MSDF Algorithm |
0; 0; 0; 0; 87; 80 | — |
| SECONDARY Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the Observed Case Analysis |
0; 0; 0; 0; 91; 86 | — |
| SECONDARY Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using the MSDF Algorithm |
0; 0; 0; 0; 48; 50 | — |
| SECONDARY Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using Observed Case Analysis |
0; 0; 0; 0; 51; 54 | — |
| SECONDARY Absolute Values for Plasma Logarithm to the Base 10 (log10) HIV-1 RNA Over Time by Visit |
4.424; 4.270; 4.428; 4.290; 1.883; 1.984 | — |
| SECONDARY Change From Baseline in Plasma log10 HIV-1 RNA Over Time by Visit |
-2.534; -2.306; -2.504; -1.875; -2.731; -2.550 | — |
| SECONDARY Number of Participants With Post-Baseline HIV-1 Associated Conditions Progression of Disease |
1; 1; 0; 0; 0; 0 | — |
| SECONDARY Absolute Values for Cluster of Differentiation 4+ (CD4+) Cell Count During Double-blind Randomized Treatment Until Week 96 |
445.5; 444.9; 459.0; 456.5; 544.0; 525.1 | — |
| SECONDARY Change From Baseline in CD4+ Cell Count Over Time by Visit |
92.6; 79.5; 91.7; 24.8; 136.4; 76.9 | — |
| SECONDARY Number of Participants With Treatment Emergent Phenotypic Resistance |
2; 0; 1; 0; 3; 1 | — |
| SECONDARY Number of Participants With Treatment Emergent Genotypic Mutations Associated With Development of Resistance |
3; 0; 1; 0; 4; 0 | — |
| SECONDARY Number of Participants With Adherence to Study Treatment |
53; 51; 55; 48; 46; 49 | — |
| SECONDARY Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 16 and Week 24 Using MSDF Algorithm-Induction Phase |
90; 83; 87; 74; 87; 85 | — |
| SECONDARY Percentage of Participants With HIV-1 RNA <50 Copies/mL From Week 24 Through Week 96 by Visit Using MSDF Algorithm-Maintenance Phase |
96; 94; 96; 96; 90; 85 | — |
| SECONDARY Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Maintenance Phase |
40; 50; 50; 35; 5; 5 | — |
| SECONDARY Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities-Maintenance Phase |
9; 12; 17; 6; 6; 6 | — |
| SECONDARY Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Maintenance Phase |
5; 5; 5; 5; 0; 1 | — |
| SECONDARY Number of Participants With AEs and SAEs Over Time |
57; 57; 60; 60; 13; 12 | — |
| SECONDARY Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities Over Time |
9; 12; 19; 8; 6; 6 | — |
| SECONDARY Number of Participants With Maximum Treatment-emergent Hematology Toxicities Over Time |
5; 5; 5; 5; 0; 1 | — |
| SECONDARY Absolute Values for ALT, AST, CK During Double-blind Randomized Treatment Until Week 96 |
23.9; 28.1; 28.5; 30.5; 24.0; 26.3 | — |
| SECONDARY Absolute Values for Creatinine and Total Bilirubin During Double-blind Randomized Treatment Until Week 96 |
80.4; 80.5; 79.9; 83.1; 83.8; 83.3 | — |
| SECONDARY Absolute Values for Estimated Creatinine Clearance During Double-blind Randomized Treatment Until Week 96 |
131.0; 135.2; 128.3; 125.6; 96.0; 106.0 | — |
| SECONDARY Absolute Values for Hemoglobin During Double-blind Randomized Treatment Until Week 96 |
141.9; 143.2; 146.6; 145.4; 142.0; 142.8 | — |
| SECONDARY Absolute Values for Platelet Count, Total Neutrophils and WBC Count During Double-blind Randomized Treatment Until Week 96 |
2.643; 2.891; 2.487; 2.441; 2.723; 2.776 | — |
| SECONDARY Change From Baseline in ALT, AST and CK Over Time by Visit |
0.1; -2.1; -1.5; -1.3; -0.7; -2.6 | — |
| SECONDARY Change From Baseline in Creatinine and Total Bilirubin Over Time by Visit |
3.36; 2.58; 4.15; 0.65; 2.24; 2.50 | — |
| SECONDARY Change From Baseline in Estimated Creatinine Clearance Over Time by Visit |
-3.0; -10.0; -0.7; -1.4; -3.7; -4.9 | — |
| SECONDARY Change From Baseline in Hemoglobin Level Over Time by Visit |
0.1; 0.0; -0.7; 0.7; -0.2; 0.5 | — |
| SECONDARY Change From Baseline in Total Neutrophils, Platelet Count and WBC Count Over Time by Visit |
0.042; -0.084; 0.104; 0.716; 0.038; -0.083 | — |
| SECONDARY Percentage of Participants Who Discontinued Investigational Product Due to Adverse Events |
7; 7; 7; 15 | — |
| SECONDARY Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings |
25; 19; 15; 10 | — |
| SECONDARY Number of Participants With AEs and SAEs-Induction Phase |
54; 54; 55; 59; 2; 0 | — |
| SECONDARY Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicity-Induction Phase |
3; 4; 13; 8; 1; 5 | — |
| SECONDARY Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Induction Phase |
1; 0; 1; 3; 0; 0 | — |
| SECONDARY Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Induction Phase |
0; 2; 5; 13 | — |
| SECONDARY Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Maintenance Phase |
2; 4; 2; 2 | — |
| SECONDARY Area Under the Concentration Time Curve Over the Dosing Interval (AUC[0-tau]) for GSK1265744 at Week 2 |
45.69; 133.74; 227.58 | — |
| SECONDARY Maximum Observed Concentration (Cmax) for GSK1265744 at Week 2 |
2.77; 7.49; 13.12 | — |
| SECONDARY Concentration at the End of a Dosing Interval (Ctau) for GSK1265744 at Week 2 |
1.45; 4.34; 5.83 | — |
| SECONDARY AUC(0 to Tau) for Rilpivirine |
— | — |
| SECONDARY Cmax for Rilpivirine |
— | — |
| SECONDARY Ctau for Rilpivirine |
— | — |
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
Data sourced from ClinicalTrials.gov (NCT01641809). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.