A Phase 3b, Randomized, Open-label Study of the Antiviral Activity and Safety of Dolutegravir Compared to Lopinavir/Ritonavir Both Administered With Dual Nucleoside Reverse Transcriptase Inhibitor Therapy in HIV-1 Infected Adult Subjects With Treatment Failure on First Line Therapy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 627
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <50 Copies Per Milliliter (c/mL) at Week 48
研究概览
简要总结
For treatment of human immunodeficiency virus type 1(HIV-1), publicly funded programmes tend to follow World Health Organization (WHO) guidelines to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs) for first-line antiretroviral therapy (ART); however, there is a need for further data on the best treatment options for people with HIV-1 who have virological failure with this first-line regimen. The number of patients failing on their first-line regimen is increasing thereby requiring a switch to second-line treatment to reduce accumulation of drug-resistance mutations, disease progression, HIV transmission, and death. WHO guidelines recommend second-line antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease inhibitor (PI); atazanavir (ATV) plus ritonavir (RTV) or lopinavir (LPV)/RTV are the preferred boosted PI options. This study is conducted to demonstrate non-inferior antiviral activity at 48 weeks of a dolutegravir (DTG) containing regimen compared to a WHO-recommended standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-1 infected patients failing first line therapy. This study comprises of a Screening Phase (approximately 28 to 42 days), a Randomized Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase. Approximately 612 subjects will be randomized 1:1 to receive DTG 50 milligram (mg) once daily or LPV/RTV (800/200 mg once daily or 400/100 mg twice daily, in accordance with investigator decision and local label), each added to an investigator selected background regimen of two NRTIs at least one of which needs to be fully active based on viral resistance testing at Screening. Subjects randomized to the LPV/RTV arm will either (i) continue receiving LPV/RTV and complete the study after the 4-week treatment extension at Week 52, or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to have access to DTG in the Continuation Phase. Subjects randomized to receive DTG who successfully complete 52 weeks of treatment and subjects originally randomized to receive LPV/RTV but switched to DTG prior to Week 52 will continue to have access to DTG until it is either locally approved and commercial supplies are available to patients or the patient no longer derives clinical benefit, or the patient meets a protocol-defined reason for discontinuation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
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
- •HIV-1 infected subjects >=18 years of age.
- •A female subject may be eligible to enter and participate in the study if she:
- •is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and >=45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or, is of child-bearing potential, with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the protocol-defined methods of contraception to avoid pregnancy throughout the study and for at least 2 weeks after discontinuation of all study medication.
- •HIV-1 infection as documented by HIV-1 RNA >=400 c/mL at Screening.
- •Subject has been on a first-line treatment regimen consisting of an NNRTI plus two NRTIs for at least 6 months and is currently experiencing virologic failure to this first-line regimen defined as two consecutive (>=7 days apart) HIV-1 RNA results of >=400 c/mL.
- •Subjects must receive at least one fully active agent within the dual-NRTI background regimen for second line treatment. Fully active is defined by the Screening genotypic resistance report of the central laboratory (or a laboratory contracted by the central laboratory) showing no evidence of full or of partial resistance for a given NRTI which will be taken on study.
- •Subject is PI-naïve and Integrase inhibitor (INI)-naïve, defined as no prior or current exposure to any PI or INI.
- •Subject or the subject's legal representative is willing and able to understand and provide signed and dated written informed consent prior to screening.
排除标准
- •Women who are breastfeeding.
- •Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic or current CD4+ cell levels <200 cells per cubic millimeter
- •Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification
- •Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase of the study.
- •History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
- •Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject.
- •Subjects who in the investigator's judgment, poses a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk.
- •Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
- •Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, systemically administered immunomodulators.
- •Treatment with any agent, other than licensed ART as allowed above with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of IP. The exception is use of entecavir, in appropriate clinical situations, for treatment of hepatitis B [e.g. prior intolerance to Tenofovir (TDF), viral resistance to lamivudine (3TC) / Emtricitabine (FTC)] after discussion and agreement between the investigator and the medical monitor.
- •Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP.
- •Any evidence of primary viral resistance to PIs or INIs based on the presence of any major resistance-associated mutation.
- •The subject's virus does not yield results using genotype at Screening (assay data is essential for eligibility determination).
- •Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 triglycerides. A single repeat test is allowed during the Screening period to verify a result.
- •Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the subject's participation in the study of an investigational compound.
- •Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN) or ALT >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin)
研究组 & 干预措施
LPV/RTV arm
Subjects will receive four oral tablets of200/50 mg LPV/RTV once daily or two oral tablets of 200/50 mg LPV/RTV twice daily plus two NRTIs selected by the investigator
干预措施: Two NRTIs (Drug)
DTG arm
Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator
干预措施: DTG (Drug)
DTG arm
Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator
干预措施: Two NRTIs (Drug)
LPV/RTV arm
Subjects will receive four oral tablets of200/50 mg LPV/RTV once daily or two oral tablets of 200/50 mg LPV/RTV twice daily plus two NRTIs selected by the investigator
干预措施: LPV/RTV (Drug)
结局指标
主要结局
Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <50 Copies Per Milliliter (c/mL) at Week 48
时间窗: Week 48
Percentage of participants with plasma HIV 1 RNA \<50 c/mL at Week 48 using the Food and Drug Administration (FDA) snapshot algorithm was assessed to demonstrate the non-inferior activity of DTG plus 2 NRTI's compared to LPV/RTV plus 2 NRTI's. Analysis was performed on Intent-to-treat exposed (ITT-E) Population, which comprised of all randomized participants who received at least one dose of study medication. Percentage values are rounded off.
次要结局
- Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24(Week 24)
- Percentage of Participants With Plasma HIV-1 RNA <400 c/mL at Weeks 24 and 48(Week 24 and Week 48)
- Percentage of Participants Without Virologic or Tolerability Failure at Week 24 and Week 48(Week 24 and Week 48)
- Time to Viral Suppression at Week 48(Week 48)
- Change From Baseline in Helper-inducer T-lymphocyte Having Surface Antigen Cluster of Differentiation (CD4+) Cell Count at Weeks 24 and 48(Baseline (Day 1, Pre-dose), Week 24 and Week 48)
- Number of Participants With Disease Progression-Randomized + Continuation Phase(Up to Week 348)
- Number of Participants With Treatment-emergent Genotypic Resistance-Randomized Phase(Up to Week 52)
- Number of Participants With Treatment-emergent Genotypic Resistance-Continuation Phase(Up to Week 295)
- Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Randomized Phase(Baseline (Day 1, Pre-dose) and up to Week 52)
- Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Continuation Phase(Baseline (Day 1, Pre-dose) and up to Week 295)
- Number of Participants With Non-serious Adverse Events (AEs) With >=2% Frequency Threshold and Serious Adverse Events (SAEs)-Randomized Phase(Up to Week 52)
- Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Continuation Phase(Up to Week 295)
- Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Randomized + Continuation Phase(Up to Week 348)
- Number of Participants With Hematology Toxicities -Randomized Phase(Up to Week 52)
- Change From Baseline in Glucose, Chloride, Carbon-di-oxide (CO2), Potassium, Phosphate, Sodium, Urea, Cholesterol, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol and Triglycerides(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52)
- Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase Values(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52)
- Change From Baseline in Albumin Values(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52)
- Change From Baseline in Creatinine and Bilirubin Values(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52)
- Change From Baseline in Lipase Values(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52)
- Number of Participants With Clinical Chemistry Toxicities -Randomized Phase(Up to Week 52)
- Number of Participants With Clinical Chemistry Toxicities-Continuation Phase(Up to Week 295)
- Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52)
- Change From Baseline in Hematocrit Values(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52)
- Change From Baseline in Hemoglobin Values(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52)
- Change From Baseline in Mean Corpuscular Volume (MCV)(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52)
- Change From Baseline in Erythrocyte Values(Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and up to Week 52)
- Number of Participants With Hematology Toxicities-Continuation Phase(Up to Week 295)
- Number of Participants Who Discontinued Treatment Due to AEs-Randomized Phase(Up to Week 52)
- Number of Participants Who Discontinued Treatment Due to AEs-Continuation Phase(Up to Week 295)
- Change From Baseline in Fasting LDL Cholesterol at Week 24 and Week 48(Baseline (Day 1, Pre-dose), Week 24 and Week 48)
- Change From Baseline in Fasting Total Cholesterol/HDL Cholesterol Ratio(Baseline (Day 1, Pre-dose), Week 24 and Week 48)
- Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Laboratory Abnormalities in Fasting LDL Cholesterol(Up to Week 48)
- Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Drug-related Diarrhea(Week 24 and Week 48)
- Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Score(Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48)
- Change From Baseline in Treatment Satisfaction, Using the HIV-Treatment Satisfaction Questionnaire (HIVTSQ) Score(Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48)
- Number of Participants Showing Adherence With Treatment, Using the Morisky 8-Item Medication Adherence Scale (MMAS-8)(Baseline (Day 1, Pre-dose), Week 4, Week 24 and Week 48)