A Phase III Randomized, Double-blind Study to Demonstrate the Antiviral Activity of Dolutegravir (DTG) 50 mg Twice Daily Versus Placebo Both Co-Administered With a Failing Antiretroviral Regimen Over Seven Days, Followed by an Open Label Phase With All Subjects Receiving DTG 50 mg Twice Daily Co-administered With an Optimised Background Regimen (OBR) in HIV-1 Infected, Integrase Inhibitor Therapy-Experienced and Resistant, Adults
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Mean Change From Baseline in Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) at Day 8
研究概览
简要总结
Study ING116529 is a multicenter, randomized, study with an initial 7 day placebo- controlled, functional monotherapy phase to quantify the antiviral activity attributable to dolutegravir (DTG) in HIV-1 infected, ART-experienced adults who are experiencing virological failure on an Integrase inhibitor containing regimen (current RAL or ELV failures), with evidence of genotypic resistance to RAL or ELV at study entry. Thirty subjects will be randomized (1:1) to receive either DTG 50mg BID (Arm A) or Placebo (Arm B) with the current failing regimen for 7 days (RAL or ELV should be discontinued prior to dosing with DTG). At Day 8, subjects from both arms will enter an open label phase and receive open label DTG 50mg BID with an optimized background regimen containing at least one fully active drug.
详细描述
Study ING116529 is a multicenter, randomized, study with an initial 7 day placebo-controlled, functional monotherapy phase to assess the antiviral activity and safety of a dolutegravir (DTG, GSK1349572) containing regimen in HIV-1 infected, ART-experienced adults with virological failure on an integrase inhibitor (INI) containing regimen.
Subjects must have evidence of genotypic resistance to raltegravir [RAL] or elvitegravir [ELV] at Screening and documented current or historical genotypic or phenotypic resistance to at least two other antiretroviral therapy drug classes.
The study is designed to provide an accurate measure of the intrinsic antiviral activity of DTG 50mg twice daily versus placebo both administered with the current failing regimen in a randomised double-blind phase to Day 8. This will be followed by an open label phase with all subjects receiving DTG 50mg twice daily with an optimized background regimen (containing at least one fully active drug) until subjects no longer derive clinical benefit or until DTG is locally available. Thirty subjects will be randomized (1:1) to receive either DTG 50mg BID (Arm A) or Placebo (Arm B) with the current failing regimen for 7 days (RAL or ELV should be discontinued prior to dosing at Day 1). At Day 8, subjects from both arms will enter an open label phase and receive open label DTG 50mg BID with an optimized background regimen containing at least one fully active drug The primary analysis will be conducted after the last subject enrolled has completed the randomised, double-blind phase at Day 8. Additional analyses may be performed prior to study closure when all ongoing subjects transition to locally available commercial DTG.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Screening plasma HIV-1 RNA ≥1000 copies/mL
- •ART-experienced, INI-experienced, DTG naïve
- •Current virological failure on raltegravir (RAL) or elvitegravir (ELV) regimen
- •The subject's HIV-1 shows genotypic resistance to RAL or ELV at Screening
- •Subject has been on stable ART for at least one month prior to Screening and through Day 1(with exceptions for ETV, EFV and NVP that can be interrupted within 14 days of Day 1, see Exclusion Criterion)
- •Documented resistance to at least one drug from each of two or more of any approved classes of ART other than integrase inhibitors
- •Be able to receive at least one fully active drug as part of the OBR from Day 8
- •Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol)
- •Willing and able to understand and provide signed and dated written informed consent prior to Screening.
排除标准
- •Women who are pregnant or breast feeding
- •An active AIDS-defining condition at Screening (except cutaneous Kaposi's sarcoma not requiring systemic therapy or CD4+ <200c/mm3)
- •Moderate to severe hepatic impairment as defined by Child-Pugh classification
- •Anticipated need for HCV therapy during the first 24 weeks of the study
- •Recent history (less than or equal to 3 months) of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding
- •Allergy or intolerance to the study drugs or their components or drugs of their class
- •Malignancy within the past 6 months
- •Treatment with an HIV-1 therapeutic vaccine within 90 days of Screening
- •Treatment with radiation therapy, cytotoxic chemotherapeutic agents or any immunomodulator within 28 days of Screening
- •Treatment with any agent, other than licensed ART, with documented in vitro/vivo activity against HIV-1 within 28 days of first dose of investigational product (with the exception of entecavir if required for Hep B treatment)
- •Treatment with etravirine, efavirenz, or nevirapine within 14 days of Day 1(etravirine may be used if coadministered with lopinavir/ritonavir or darunavir/ritonavir)
- •Treatment with tipranivir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir within 28 days prior to Screening
- •Exposure to an experimental drug or vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, which ever is longer, prior to the first dose of IP.
- •Any acute or verified Grade 4 laboratory abnormality (with the exception of Grade 4 lipids) at Screening
- •ALT> 5 times the upper limit of normal (ULN) at Screening
- •ALT ≥ 3X ULN and bilirubin > 1.5 X ULN (with 35% direct bilirubin) at Screening
研究组 & 干预措施
DTG 50 mg BID
Subjects will receive dolutegravir (DTG) 50 milligrams (mg) twice daily (BID) and the components of their current failing antiretroviral regimen, except raltegravir or elvitegravir, for 7 days during the Double-blind (DB) Phase. From Day 8, all subjects will continue to receive DTG 50 mg BID with an optimized background regimen in the Open-label Phase.
干预措施: Dolutegravir 50 mg twice daily (Drug)
Placebo BID in DB Phase; DTG 50 mg BID in Open-label Phase
Subjects will receive matching placebo BID and the components of their current failing antiretroviral regimen, except raltegravir or elvitegravir, for 7 days during the DB Phase. From Day 8, all subjects will continue to receive DTG 50 mg BID with an optimized background regimen in the Open-label Phase.
干预措施: Dolutegravir 50 mg twice daily (Drug)
Placebo BID in DB Phase; DTG 50 mg BID in Open-label Phase
Subjects will receive matching placebo BID and the components of their current failing antiretroviral regimen, except raltegravir or elvitegravir, for 7 days during the DB Phase. From Day 8, all subjects will continue to receive DTG 50 mg BID with an optimized background regimen in the Open-label Phase.
干预措施: Dolutegravir placebo twice daily (Drug)
结局指标
主要结局
Mean Change From Baseline in Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) at Day 8
时间窗: Baseline and Day 8
Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1) and Day 8. Change from Baseline was calculated as the value at Day 8 minus the value at Baseline (Day 1). The analysis was performed using statistical modeling correcting for Baseline plasma HIV-1 RNA, Baseline Dolutegravir (DTG) fold change (FC), the overall susceptibility score (OSS) of the failing regimen, and the interaction between DTG FC and treatment. Means and differences were calculated using the average Baseline DTG FC of the entire Intent-to-Treat Exposed (ITT-E) Population. The last observation carried forward with discontinuation equals Baseline (LOCFDB) dataset was used for the analysis. For the LOCFDB dataset, missing values were carried forward from the previous, non-missing, available on-treatment assessment, except formissing values due to premature withdrawal or Day 8 missing values, which had the Baseline value imputed.
次要结局
- Change From Baseline in Cholesterol, Chloride, Carbon Dioxide (CO2)/Bicarbonate (HCO3), Glucose, High Density Lipoprotein Cholesterol, Potassium, Low Density Lipoprotein (LDL) Cholesterol, Sodium, Phosphorus, Triglycerides and Urea/Blood Urea Nitrogen(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)
- Change From Baseline in Creatinine Clearance(Baseline, Day 8, Day 28, Week 8, Week 16, Week 24, Week 32 and Week 48)
- Change From Baseline in Lipase Levels(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)
- Change From Baseline in Hematocrit Level(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)
- Change From Baseline in Mean Corpuscle Volume(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)
- Change From Baseline in Red Blood Cell Count(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)
- Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet and White Blood Cell (WBC) Count(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)
- Change From Baseline in Hemoglobin Level(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)
- Absolute Values in Plasma HIV-1 RNA Over Time(Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84)
- Number of Participants With Plasma HIV-1 RNA <50 c/mL Over Time(Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40 and 48)
- Absolute Values in Cluster of Differentiation 4+ (CD4+) Cell Counts Over Time(Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84)
- Mean Change From Baseline in Plasma HIV-1 RNA Over Time(Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84)
- Number of Participants With Plasma HIV-1 RNA <400 c/mL Over Time(Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40 and 48)
- Absolute Values in Cluster of Differentiation 8+ (CD8+) Cell Counts Over Time(Baseline; Day 28; Weeks 12, 24, and 48)
- Median Change From Baseline in CD4+ Cell Counts Over Time(Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84)
- Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade(From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks))
- Cmax of DTG(Day 8, Day 28, and Week 24)
- Median Change From Baseline in CD8+ Cell Counts Over Time(Baseline; Day 28; Weeks 12, 24, and 48)
- AUC(0-tau) of DTG(Day 8, Day 28, and Week 24)
- Plasma DTG Pre-dose Concentration (C0) at Day 8, Day 28, and Week 24; and Average DTG C0 (C0 Avg) at Week 24(Day 8, Day 28, and Week 24)
- Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Defined Virologic Failure (PDVF), as a Measure of Genotypic Resistance(From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks))
- Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings(Up to Week 24)
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Baseline and Weeks 24 and 48)
- Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Creatine Kinase(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)
- Number of Participants With the Indicated Type of HIV-1 Disease Progression (Acquired Immunodeficiency Syndrome [AIDS] or Death [DT])(From the day of the first dose of study drug until early withdrawal or the Week 48 analysis cut-off date (median of 55 study weeks))
- Number of Participants With Any Adverse Event (Serious and Non-serious) of the Indicated Grade(From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks))
- Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade(From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks))
- Number of Participants With the Indicated Fold Increase in Fold Change (FC) in the 50% Inhibitory Concentration Relative to Wild-type Virus for DTG (i.e. PDVF FC/Baseline FC Ratio) at the Time of PDVF, as a Measure of Phenotypic Resistance(From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks))
- Number of Participants Who Discontinued Study Treatment Due to AEs(From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks))
- Change From Baseline in Heart Rate(Baseline and Weeks 24 and 48)
- Change From Baseline in Albumin Level(Baseline, Week 24 and 48)
- Change From Baseline in Total Bilirubin (T. Bil) and Creatinine Levels(Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84)