NCT02429791已完成3 期
A Phase III, Randomized, Multicenter, Parallel-group, Non-inferiority Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Dolutegravir Plus Rilpivirine From Current INI-, NNRTI-, or PI-based Antiretroviral Regimen in HIV-1-Infected Adults Who Are Virologically Suppressed
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 510
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 48 Using Snapshot Algorithm
研究概览
简要总结
The aim of this study is to determine if virologically suppressed human immunodeficiency virus type 1 (HIV-1) infected adults on an antiretroviral regimen (including 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus a third agent) remain suppressed upon switching to a two-drug regimen with dolutegravir (DTG) + rilpivirine (RPV). The study will primarily assess the non-inferiority antiviral activity of switching to DTG + RPV once daily compared to continuation of current antiretroviral regimen (CAR) up to Week 48 with a switch visit for eligible subjects in the CAR group to initiate DTG + RPV therapy at Week 52. CAR will include 2 NRTIs plus 1 HIV-1 integrase inhibitor (INI), or 1 non-nucleoside reverse transcriptase inhibitor (NNRTI), or 1 protease inhibitor (PI). The study will include a 148-week open-label treatment phase, comprising of an Early Switch Phase (Day 1 to Week 52) and a Late Switch Phase (Week 52 to Week 148). The participants fulfilling the study eligibility criteria will participate in the Early Switch Phase where they will either switch from their CAR to DTG + RPV, or continue taking their CAR, until Week 52. At the end of Early Switch Phase, eligible participants will proceed to the Late Switch Phase where all participants in both DTG + RPV and CAR treatment groups will receive DTG + RPV therapy until Week 148. After Week 148, subjects may be eligible to continue to receive DTG +RPV in the Continuation Phase. The study is planned to be conducted in approximately 476 participants.
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
- •Participants must be able to understand and comply with protocol requirements, instructions, and restrictions.
- •Participants must be likely to complete the study as planned.
- •Participants must be considered appropriate candidates for participation in an investigative clinical trial with oral medication (e.g., no active substance abuse, acute major organ disease, or planned long-term work assignments out of the country, etc.).
- •HIV-1 infected men or women of >=18 years of age.
- •Must be on uninterrupted current regimen (either the initial or second combination antiretroviral therapy [cART] regimen) for at least 6 months prior to screening; Any prior switch, defined as a change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability and/or safety concerns or access to medications, or convenience/simplification. Acceptable stable cART regimens prior to screening include 2 NRTIs plus INI (either the initial or second cART regimen), or an NNRTI (either the initial or second cART regimen), or a Boosted PI (or atazanavir unboosted) (either the initial or second PI-based cART regimen).
- •Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening;
- •Plasma HIV-1 RNA <50 c/mL at Screening;
- •A female may be eligible to enter and participate in the study if she is of : Non-child-bearing potential either defined as 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, Child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy: Complete abstinence from intercourse from 2 weeks prior to administration of study drug, throughout the study, and for at least 2 weeks after discontinuation of all study medications and completion of the Follow-up visit; Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion); Male partner sterilization with documentation of azoospermia prior to the female participant's entry into the study and this male is the sole partner for that participant; The documentation on male sterility can come from the site personnel's review of participant's medical records, medical examination, and/or semen analysis, or medical history interview provided by her or her partner; Approved hormonal contraception for participants randomly assigned to DTG + RPV arm (and for participants randomly assigned to CAR following switch to DTG + RPV at Week 52) or approved hormonal contraception plus a barrier method for participants assigned to CAR through Week 52; Approved hormonal contraception includes: Combined estrogen and progestogen oral contraceptive, Contraceptive subdermal implant, Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches. Any other method with published data showing that the expected failure rate is <1% per year. Any contraception method must be used consistently, in accordance with the approved product label during treatment with study drug and for at least 2 weeks after discontinuation of study drug and completion of the Follow-Up Visit. The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Note: these contraceptive requirements do not apply to females of reproductive potential with same sex partners only, when this is their preferred and usual lifestyle. All participants participating in the study should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to an uninfected partner.
- •Participants who are willing and able to understand requirements of study participation and provide signed and dated written informed consent prior to screening.
- •For participants enrolled in France: participants will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
排除标准
- •Exclusionary Criteria prior to screening or Day 1:
- •Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement >=50 c/mL.
- •Within the 6 to 12 month window prior to screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.
- •Within the 6 to 12 month window prior to screening and after confirmed suppression to <50 c/mL, 2 or more plasma HIV-1 RNA measurements >=50 c/mL.
- •Any drug holiday during the window between initiating first HIV ART and 6 months prior to screening, except for brief periods (less than 1 month) where all ART was stopped due to tolerability and/or safety concerns.
- •Any switch to a second line regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV 1 RNA measurement >=400 c/mL after initial suppression to <50 c/mL while on first line HIV therapy regimen).
- •Exclusionary medical conditions:
- •Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the study.
- •Any evidence of an active Centers for Disease Control and Prevention Category C disease. Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic CD4+ lymphocyte counts of <200 cells per cubic millimeter (cells/mm^3).
- •Participants with severe hepatic impairment (Class C) as determined by Child-Pugh Classification.
- •Unstable liver disease (as defined by the presence of any of the following: ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •Evidence of Hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), and Hepatitis B surface antibody (HBsAb) as follows: Participants positive for HBsAg are excluded; Participants positive for anti-HBc (negative HBsAg status) and negative for HBsAb are excluded. Note: Participant positive for anti-HBc (negative HBsAg status) and positive for HBsAb are immune to HBV and are not excluded.
- •Participants with an anticipated need for any Hepatitis C virus (HCV) therapy during the Early Switch Phase and for interferon-based therapy for HCV throughout the entire study period.
- •History or presence of allergy 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 participant prior to randomization;
- •Participants who in the investigator's judgment pose a significant suicidality risk. Participant's history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk;
- •Any pre-existing physical or mental condition which, in the opinion of the Investigator, may interfere with the participant's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participants;
- •Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the participant unable to take oral medication;
- •Exclusionary Treatments prior to Screening or Day 1:
- •Use of medications which are associated with Torsades de Pointes.
- •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; any immunomodulators that alter immune responses.
- •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 Day 1 of this study.
- •Participants who are currently participating or are anticipated to be selected to participate in any other interventional study, with the exception of the DEXA sub-study 202094, after randomization (NOTE: Participants who are already enrolled into another interventional study at time of screening may be eligible after consultation with the GlaxoSmithKline study team prior to randomization. Considerations include participant's ability to attend all visits on schedule, and possible drug and study procedure compatibility).
- •A history of use of any regimen consisting of only single NNRTI therapy (even if only for peri-partum treatment), or only single or dual NRTI therapy prior to starting cART.
- •Current or prior history of etravirine (ETR) use.
- •Current use of tipranavir/ritonavir or fosamprenavir/ritonavir.
- •Participants receiving any prohibited medication and who are unwilling or unable to switch to an alternate medication. Note: Any prohibited medications that decrease DTG or RPV concentrations should be discontinued for a minimum of four weeks or a minimum of three half-lives (whichever is longer) prior to the first dose and any other prohibited medications should be discontinued for a minimum of two weeks or a minimum of three half-lives (whichever is longer) prior to the first dose.
- •Exclusionary Laboratory Values or Clinical Assessments at Screening:
- •Evidence of viral resistance based on the presence of any resistance associated major PI, INI, NRTI, or NNRTI mutation and integrase (IN) resistance associated substitution R263K in any available prior resistance genotype assay results. Note: Prior genotypic resistance testing is not required but if available it must be provided to GlaxoSmithKline, after screening and before randomization, to provide direct evidence of no pre-existing exclusionary resistance mutations. You must wait for the study virologists to confirm the lack of exclusionary resistance mutations, which will be provided before the screening window closes.
- •Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid abnormalities. 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 participant's participation in the study of an investigational compound.
- •Alanine aminotransferase (ALT) >=5 × upper limit of normal (ULN), or ALT >=3 × ULN and bilirubin >=1.5 × ULN (with >35% direct bilirubin).
- •Corrected QT interval (QTc [Bazett]) >450 milliseconds or QTc (Bazett) >480 milliseconds for participants with bundle branch block. The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB).
研究组 & 干预措施
Current antiretroviral regimen (CAR)
Active Comparator
Participants continued to receive their CAR (two nucleoside reverse transcriptase inhibitors [NRTIs] + a third agent). A third agent included either an: integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). CAR was administered according to the approved labeling in an open-label fashion up to Week 52 during the Early Switch Phase. At Week 52, participants with human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) less than (<) 50 copies (c)/mL, switched to DTG 50 mg + RPV 25 mg once daily and were followed-up through the Late Switch Phase, at Week 148 and through the Continuation Phase, after Week 148.
干预措施: CAR (Drug)
DTG + RPV
Experimental
Participants received DTG 50 mg + RPV 25 mg together, once daily, at approximately the same time, with a meal, in an open-label fashion up to Week 52, during the Early Switch Phase. Participants continued to receive DTG 50 mg + RPV 25 mg up to Week 148 during the Late Switch Phase. Participants who successfully completed 148 weeks of treatment were given the opportunity to continue to receive DTG + RPV once daily in the Continuation Phase (after Week 148).
干预措施: DTG 50 mg (Drug)
DTG + RPV
Experimental
Participants received DTG 50 mg + RPV 25 mg together, once daily, at approximately the same time, with a meal, in an open-label fashion up to Week 52, during the Early Switch Phase. Participants continued to receive DTG 50 mg + RPV 25 mg up to Week 148 during the Late Switch Phase. Participants who successfully completed 148 weeks of treatment were given the opportunity to continue to receive DTG + RPV once daily in the Continuation Phase (after Week 148).
干预措施: RPV 25 mg (Drug)
结局指标
主要结局
Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 48 Using Snapshot Algorithm
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 antiviral activity of switching to DTG + RPV once daily compared to continuation of CAR over 48 weeks in HIV-1 infected antiretroviral therapy (ART)-experienced participants. Virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment within the window of the visit of interest. Plasma samples were collected for quantitative analysis of HIV-1 RNA.
次要结局
- Changes From Baseline in Cluster Designation (CD)4+ Lymphocyte Count at Weeks 24 and 48(At Weeks 24 and 48)
- Percentage of Participants With Plasma HIV 1 RNA <50 c/mL at Week 24 Using Snapshot Algorithm(Week 24)
- Number of Participants With Common Non-serious Adverse Event (AE), Any Serious AE (SAE), AE of Maximum Toxicity Grade 1, 2, 3 or 4 and AE Leading to Discontinuation (AELD)(Up to Week 411 or study discontinuation)
- Number of Participants With Maximum Post-baseline Emergent Chemistry Toxicities Over 48 Weeks(Up to 48 weeks)
- Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities Over 48 Weeks(Up to 48 weeks)
- Mean Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) at Week 48(At Week 48)
- Mean Change From Baseline in Cystatin C at Week 48(At Week 48)
- Mean Change From Baseline in D-Dimer at Week 48(At Week 48)
- Mean Change From Baseline in Fatty Acid Binding Protein 2 (FABP) and Soluble Cluster Designation (CD)14 at Week 48(At Week 48)
- Number of Participants With Any AE, AELD or AE With Grade 1, 2, 3 or 4 Toxicity Over 48 Weeks by Baseline Third Agent Treatment Class(Up to 48 weeks)
- Number of Participants With Maximum Post-baseline Emergent Chemistry Toxicities Over 48 Weeks by Baseline Third Agent Treatment Class(Up to 48 weeks)
- Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities Over 48 Weeks by Baseline Third Agent Treatment Class(Up to 48 weeks)
- Mean Change From Baseline in Soluble CD163 and Oxidized Low Density Lipoprotein (LDL) at Week 48(At Week 48)
- Mean Change From Baseline in Retinol Binding Protein (RBP), Serum Creatinine and Glucose at Week 48(At Week 48)
- Mean Change From Baseline in Urine Phosphate at Week 48(At Week 48)
- Mean Change From Baseline in Beta-2-microglobulin (B2M) (Blood and Urine), Urine RBP and 25 Hydroxy-vitamin D (Blood) at Week 48(At Week 48)
- Mean Change From Baseline in Urine Albumin/Creatinine Ratio and Urine Protein/Creatinine Ratio at Week 48(At Week 48)
- Mean Change From Baseline in Bone-specific Alkaline Phosphatase, Procollagen 1 N-terminal Propeptide, Osteocalcin, Type I Collagen C-Telopeptides and Soluble Vascular Cell Adhesion Molecule (sVCAM) at Week 48(At Week 48)
- Mean Change From Baseline in Interleukin 6 (IL-6) at Week 48(At Week 48)
- Mean Change From Baseline in Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Week 48(At Week 48)
- Mean Change From Baseline in Fasting Lipids at Weeks 24 and 48(At Week 24 and at Week 48)
- Number of Participants With Genotypic Resistance- Early Switch Phase(Up to Week 52)
- Number of Participants With Genotypic Resistance-DTG+RPV Group Through Early and Late Switch Phase(Up to Week 148)
- Number of Participants With Genotypic Resistance-CAR Group Through Late Switch Phase(Post-Late switch (LS) Baseline (Week 52) up to Week 148)
- Number of Participants With Phenotypic Resistance-Early Switch Phase(Up to Week 52)
- Number of Participants With Phenotypic Resistance-DTG+RPV Group Through Early and Late Switch Phase(Up to Week 148)
- Number of Participants With Phenotypic Resistance-CAR Group Through Late Switch Phase(Post-LS Baseline (Week 52) up to Week 148)
- Pre-dose Concentrations of DTG and RPV at Weeks 4, 24, 48, 56, 76 and 100 in Participants Switching to DTG + RPV-DTG+RPV Group Through Early and Late Switch Phase(Pre-dose at Week 4, 24, 48, 56, 76 and 100)
- Pre-dose Concentrations of DTG and RPV at Weeks 56, 76 and 100 in Participants Switching to DTG+RPV-CAR Group Through Late Switch Phase(Pre-dose at Weeks 56, 76 and 100)
- Pre-dose Concentrations of DTG and RPV at Weeks 2, 4 and 8 in the First 20 Participants Who Switch From Efavirenz (EFV) or Nevirapine (NVP) to DTG + RPV(Pre-dose at Week 2, 4 and 8)
- Percentage of Participants With Plasma HIV 1 RNA <50 c/mL at Week 48 Using Snapshot Algorithm by Baseline Third Agent Treatment Class(Week 48)
- Changes From Baseline in Cluster Designation (CD)4+ Lymphocyte Count at Week 48 by Baseline Third Agent Treatment Class(At Week 48)
- Number of Participants With Observed Genotypic Resistance for Participants Meeting Virologic Withdrawal Criteria by Baseline Third Agent Treatment Class(Up to Week 48)
- Number of Participants With Observed Phenotypic Resistance for Participants Meeting Virologic Withdrawal Criteria by Baseline Third Agent Treatment Class(Up to Week 48)
- Change From Baseline in Fasting Lipids at Weeks 24 and 48 by Baseline Third Agent Treatment Class(At Week 24 and at Week 48)
- Change From Baseline in Pre-specified Treatment Symptoms Using the Symptom Distress Module at Weeks 4, 24 and 48-Early Switch Phase(At Week 4, Week 24 and Week 48)
- Change From Baseline in Pre-specified Treatment Symptoms Using the Symptom Distress Module at Weeks 56, 76, 100 and 148-DTG+RPV Group Through Early and Late Switch Phase(At Week 56, Week 76, Week 100 and Week 148)
- Change From LS Baseline in Pre-specified Treatment Symptoms Using the Symptom Distress Module at Weeks 56, 76, 100 and 148-CAR Group Through Late Switch Phase(At Week 56, Week 76, Week 100 and Week 148)
- Change From Baseline Treatment Satisfaction Using the HIV Treatment Satisfaction Questionnaire (HIV TSQ) at Weeks 4, 24 and 48-Early Switch Phase(At Week 4, Week 24 and Week 48)
- Change From Baseline Treatment Satisfaction Using HIV TSQ at Weeks 56, 76, 100 and 148 - DTG+RPV Group Through Early and Late Switch Phase(At Week 56, Week 76, Week 100 and Week 148)
- Change From LS Baseline Treatment Satisfaction Using HIV TSQ at Weeks 56, 76, 100 and 148-CAR Group Through Late Switch Phase(At Week 56, Week 76, Week 100 and Week 148)
- Number of Participants With Observed Genotypic Resistance for Participants Meeting Virologic Withdrawal Criteria by Baseline Third Agent Treatment Class-DTG+RPV Group Through Continuation Phase(Up to Week 411)
- Number of Participants With Observed Phenotypic Resistance for Participants Meeting Virologic Withdrawal Criteria by Baseline Third Agent Treatment Class-DTG+RPV Group Through Continuation Phase(Up to Week 411)
- Number of Participants With Observed Genotypic Resistance for Participants Meeting Virologic Withdrawal Criteria by Baseline Third Agent Treatment Class- CAR Group Through Continuation Phase(Week 52 to Week 411)
- Number of Participants With Observed Phenotypic Resistance for Participants Meeting Virologic Withdrawal Criteria by Baseline Third Agent Treatment Class- CAR Group Through Continuation Phase(Week 52 to Week 411)
- Number of Participants With Genotypic Resistance-DTG+RPV Group Through Continuation Phase(Up to Week 411)
- Number of Participants With Phenotypic Resistance-DTG+RPV Group Through Continuation Phase(Up to Week 411)
- Number of Participants With Genotypic Resistance-CAR Group Through Continuation Phase(Week 52 to Week 411)
- Number of Participants With Phenotypic Resistance- CAR Group Through Continuation Phase(Week 52 to Week 411)
研究者
研究点 (1)
Loading locations...
相似试验
已完成
3 期
Regimen Switch to Dolutegravir + Rilpivirine From Current Antiretroviral Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults (SWORD-2)HIV InfectionsNCT02422797ViiV Healthcare518
已完成
3 期
Regimen Switch to Dolutegravir/Lamivudine Fixed Dose Combination From Current Antiretroviral Regimen in HIV-1 Infected and Virologically Suppressed Adults (SALSA)HIV InfectionsNCT04021290ViiV Healthcare493
已完成
2 期
Therapeutic Intensification Plus Immunomodulation to Decrease the HIV-1 Viral ReservoirHIV InfectionNCT00976404Robert L. Murphy28
已完成
3 期
Switch Study to Evaluate Dolutegravir Plus Lamivudine in Virologically Suppressed Human Immunodeficiency Virus Type 1 Positive Adults (TANGO)HIV InfectionsNCT03446573ViiV Healthcare743
已完成
4 期
Study of Reyataz in HIV-infected Patients With Lipodystrophy SyndromeHIV-Associated Lipodystrophy SyndromeNCT00135356Bristol-Myers Squibb219