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临床试验/NCT03446573
NCT03446573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 Lamivudine in HIV-1 Infected Adults Who Are Virologically Suppressed

ViiV Healthcare1 个研究点 分布在 1 个国家目标入组 743 人开始时间: 2018年1月18日最近更新:
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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
743
试验地点
1
主要终点
Percentage of Participants With Virologic Failure Endpoint as Per Food and Drug Administration (FDA) Snapshot Category at Week 48
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

The aim of the study is to establish if human immunodeficiency virus type 1 (HIV-1) infected adult participants with current virologic suppression on a >=3-drug tenofovir alafenamide (TAF) based regimen (TBR) remain suppressed upon switching to a two-drug regimen of dolutegravir (DTG) 50 milligram (mg) + lamivudine (3TC) 300 mg. This study will also provide important information regarding the safety and participant satisfaction with this two-drug regimen. The primary objective of this trial is to demonstrate the non-inferior antiviral activity of switching to DTG + 3TC once daily compared to continuation of TBR over 48 weeks in HIV-1 infected, antiretroviral therapy (ART)-experienced, virologically suppressed participants. This study also will characterize the long-term antiviral activity, tolerability and safety of DTG + 3TC compared to TBR through Week 144 and characterize the long-term antiviral activity, tolerability and safety of DTG + 3TC through Week 200.

This will be a 200-week, Phase III, randomized, open-label, active-controlled, multicenter, parallel- group study. The study will include a screening phase (up to 28 days), a randomized early switch phase (Day 1 up to Week 148), a randomized late switch phase (Week 148 up to Week 200), and a continuation phase (post Week 200). HIV-1 infected adults on stable TBR will be randomized 1:1 to switch to DTG + 3TC once daily for up to 200 weeks, or to continue their TBR for 148 weeks, at which time and if HIV-1 ribonucleic acid (RNA) <50 copies per milliliter (c/mL) at Week 144, these participants will switch to DTG + 3TC up to Week 200.

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

盲法说明

This will be an open-label study and therefore no blinding is required. No summaries of the study data according to actual randomized treatment groups will be available to sponsor staff prior to the planned Week 24 preliminary analysis.

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

  • •Participant must be able to understand and comply with protocol requirements, instructions, and restrictions;
  • •Participant must be likely to complete the study as planned;
  • •Participant must be considered an appropriate candidate for participation in an investigative clinical trial with medication (example no active substance abuse, acute major organ disease, or planned long-term work assignments out of the country).
  • •Aged 18 years or older (or older where required by local regulatory agencies), at the time of signing the informed consent.
  • •HIV-1 infected men or women.
  • •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.
  • •Must be on uninterrupted ART for at least 6 months prior to screening. Only the following regimens are allowed:
  • •Participant on a TAF-based regimen for at least 6 months as the initial regimen, or
  • •Participants who switched from a tenofovir disoproxil fumarate (TDF) first-regimen TAF, without any changes to the other drugs in their regimen, and have been on the TAF-based regimen for at least 3 months immediately prior to Screening i.e., the only switch made is from TDF to TAF. This switch must have occurred due to tolerability/safety, access to medications, or convenience/simplification, and must NOT have been done for suspected or established treatment failure. A switch from a PI boosted with ritonavir to the same PI boosted with cobicistat is allowed (and vice versa).
  • •A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test at screen and a negative urine hCG test at randomization [a local serum hCG test at Randomization is allowed if it can be done, and results obtained, within 24 hours prior to randomization]), not lactating, and at least one of the following conditions applies:
  • •a. Non-reproductive potential defined as:
  • •Pre-menopausal females with one of the following:
  • •Documented tubal ligation
  • •Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
  • •Hysterectomy
  • •Documented bilateral oophorectomy
  • •Post-menopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] and estradiol levels consistent with menopause [refer to laboratory reference ranges for confirmatory levels]). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
  • •b. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and for at least 2 weeks after the last dose of study medication.
  • •The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception. 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.
  • •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and the protocol. Eligible participants or their legal guardians must sign a written informed consent form before any protocol-specified assessments are conducted.
  • •Participants enrolled in France must be affiliated to, or a beneficiary of, a social security category.

排除标准

  • •Women who are breastfeeding or plan to become pregnant or breastfeed during the study.
  • •Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 disease, EXCEPT cutaneous Kaposi's sarcoma not requiring systemic therapy. Historical or current CD4 cell counts less than 200 cells/millimeter (mm)^3 are NOT exclusionary.
  • •Participants 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).
  • •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), Hepatitis B surface antigen antibody (anti-HBs) and HBV deoxyribonucleic acid (DNA) as follows: participants positive for HBsAg are excluded; participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.
  • •Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of the study, or anticipated need for HCV therapy based on interferon or for any drugs that have a potential for adverse drug-drug interactions with study treatment throughout the entire study period.
  • •Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of treatment). Participants who are at least 7 days post completed treatment are eligible.
  • •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, anal or penile intraepithelial neoplasia.
  • •Participants who in the investigator's judgment, poses a significant suicidality 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; any systemic immune suppressant.
  • •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 investigational product (IP).
  • •Use of any regimen consisting of single or dual ART.
  • •Any evidence of major nucleoside reverse transcriptase inhibitor (NRTI) mutation or presence of any major INSTI resistance-associated mutation in any available prior resistance genotype assay test result, if known, must be provided to ViiV after screening and before randomization for review by ViiV Virology.
  • •Any verified Grade 4 laboratory abnormality.
  • •Alanine aminotransferase (ALT) >=5 times (*) the upper limit of normal (ULN) or ALT >=3 * ULN and bilirubin >=1.5 * ULN (with >35 percent [%] direct bilirubin).
  • •Creatinine clearance of <50 milliliter (mL)/minute/1.73 meter^2 via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method.
  • •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.
  • •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.
  • •Any drug holiday during the 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 history of switch to another 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 ≥400 c/mL.
  • •Participants enrolled in France (or in other countries as required by local regulations or Ethics Committee/Institutional Review Board [IRB]) who:
  • •Participated in any study using an investigational drug or vaccine during the previous 60 days or 5 half-lives, or twice the duration of the biological effect of the experimental drug or vaccine, whichever is longer, prior to screening for the study, or
  • •Participate simultaneously in another clinical study.

研究组 & 干预措施

DTG + 3TC 50 mg/300 mg

Experimental

Participants will receive a single tablet of a two-drug regimen of DTG 50 mg + 3TC 300 mg once daily from Day 1 through Week 200 (Early and Late Switch Phase).

干预措施: DTG + 3TC (Drug)

TAF based regimen (TBR)

Active Comparator

Participants will continue their TBR from Day 1 to Week 148 (Early Switch Phase), and eligible participants will switch to DTG + 3TC once daily from Week 148 to 200 (Late Switch Phase).

干预措施: TAF based regimen (TBR) (Drug)

结局指标

主要结局

Percentage of Participants With Virologic Failure Endpoint as Per Food and Drug Administration (FDA) Snapshot Category at Week 48

时间窗: Week 48

Percentage of participants with virologic failure (plasma HIV-1 RNA \>=50 c/mL) was evaluated using FDA snapshot algorithm at Week 48. The Snapshot algorithm treated all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to the visit window) as non-responders, as well as participants who switch their concomitant antiretroviral therapy (ART) prior to the visit of interest. Intent-to-treat exposed (ITT-E) Population comprises of all randomized participants who received at least one dose of study treatment either DTG + 3TC or TBR. Participants were assessed according to the treatment to which the participant was randomized. Any participant receiving a treatment randomization number was considered to be randomized.

次要结局

  • Change From Baseline in CD4+/CD8+ Cell Count Ratio at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in CD4+/CD8+ Cell Count Ratio at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Percentage of Participants With Virologic Failure Endpoint as Per FDA Snapshot Category at Week 24(Week 24)
  • Percentage of Participants With Virologic Failure Endpoint as Per FDA Snapshot Category at Weeks 96, 144(Weeks 96 and 144)
  • Change From Baseline in CD4+ Cell Count at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Number of Participants With Disease Progression at Weeks 96 and 144(At Weeks 96 and 144)
  • Percentage of Participants With Plasma HIV-1 RNA <50 c/mL as Per Snapshot Algorithm at Weeks 96 and 144(Weeks 96 and 144)
  • Percentage of Participants With Plasma HIV-1 RNA <50 c/mL as Per Snapshot Algorithm at Week 48(Week 48)
  • Percentage of Participants With Plasma HIV-1 RNA <50 c/mL as Per Snapshot Algorithm at Week 24(Week 24)
  • Number of Participants Who Discontinued the Treatment Due to AEs: Up to Week 144(Up to Week 144)
  • Change From Baseline in Fasting Lipids at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
  • Number of Participants With Phenotypic Resistance: Up to Week 48(Up to Week 48)
  • Number of Participants With Phenotypic Resistance: Up to Week 144(Up to Week 144)
  • Number of Participants With Disease Progression at Weeks 24 and 48(At Weeks 24 and 48)
  • Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen Who Discontinued the Treatment Due to AEs: Up to Week 48(Up to Week 48)
  • Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities: Up to Week 48(Up to Week 48)
  • Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities: Up to Week 144(Up to Week 144)
  • Change From Baseline in Renal Biomarkers- Urine Albumin/Creatinine (UA/C) Ratio and Urine Protein/Creatinine (UP/C) Ratio at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
  • Change From Baseline in Renal Biomarkers- Urine Beta-2 Microglobulin/Urine Creatinine Ratio at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
  • Change From Baseline in CD4+ Cell Count at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Number of Participants With Any SAEs and Common (>=2%) Non-SAEs: Up to Week 148(Up to Week 148)
  • Number of Participants With AEs by Their Severity Grades: Up to Week 48(Up to Week 48)
  • Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen With AEs by Their Severity Grades: Up to Week 48(Up to Week 48)
  • Change From Baseline in Renal Biomarkers- UA/C Ratio and UP/C Ratio at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Number of Participants With Any Serious Adverse Events (SAEs) and Common (>=2%) Non-serious Adverse Events (Non-SAEs): Up to Week 48(Up to Week 48)
  • Number of Participants With Maximum Post-Baseline Emergent Clinical Chemistry Toxicities: Up to Week 48(Up to Week 48)
  • Number of Participants With Maximum Post-Baseline Emergent Clinical Chemistry Toxicities: Up to Week 144(Up to Week 144)
  • Change From Baseline in Renal Biomarkers- Urine Beta-2 Microglobulin/Urine Creatinine Ratio at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
  • Number of Participants With Genotypic Resistance: Up to Week 144(Up to Week 144)
  • Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen With Any SAEs and Common (>=2%) Non-SAEs: Up to Week 48(Up to Week 48)
  • Number of Participants With AEs by Their Severity Grades: Up to Week 144(Up to Week 144)
  • Number of Participants Who Discontinued the Treatment Due to AEs: Up to Week 48(Up to Week 48)
  • Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen With Maximum Post-Baseline Emergent Hematology Toxicities: Up to Week 36(Up to Week 36)
  • Number of Participants Randomized to TBR Arm Receiving TDF-based Regimen With Maximum Post-Baseline Emergent Clinical Chemistry Toxicities: Up to Week 36(Up to Week 36)
  • Change From Baseline in Renal Biomarkers- UA/C Ratio and UP/C Ratio at Weeks 24 and 48 in Participants Randomized to TBR Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
  • Change From Baseline in Renal Biomarkers- Urine Beta-2 Microglobulin/Urine Creatinine Ratio at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Renal Biomarkers- Urine Phosphate at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
  • Change From Baseline in Renal Biomarkers- Urine Phosphate at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Renal Biomarkers- Urine Retinol Binding Protein 4/Urine Creatinine at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
  • Number of Participants With Genotypic Resistance: Up to Week 48(Up to Week 48)
  • Change From Baseline in Fasting Lipids at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at weeks 24 and 48)
  • Change From Baseline in Bone Biomarkers-serum Bone-specific ALP (Bone-ALP), Osteocalcin, Serum Procollagen 1 N-Terminal Propeptide (P1NP) and Serum Type 1 Collagen C-telopeptides (CTX-1) at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Bone Biomarkers-serum Bone-ALP, Osteocalcin, Serum P1NP and Serum Type 1 CTX-1 at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Renal Biomarkers- Urine Phosphate at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
  • Change From Baseline in Renal Biomarkers- Urine Retinol Binding Protein 4/Urine Creatinine at Weeks 24 and 48(Baseline (Day 1) and at weeks 24 and 48)
  • Change From Baseline in Renal Biomarkers- Urine Retinol Binding Protein 4/Urine Creatinine at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Fasting Lipids at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Bone Biomarkers-serum Bone-specific ALP (Bone-ALP), Osteocalcin, Serum P1NP and Serum CTX-1 in Participants Randomized to TBR Arm Receiving TDF-based Regimen at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Renal Biomarker- Serum Cystatin C at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Renal Biomarker- Serum Creatinine at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Bone Biomarker: Serum 25-hydroxyvitamin D at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Bone Biomarker: Serum 25-hydroxyvitamin D at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score at Week 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in EQ-5D-5L Thermometer Scores at Week 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in EQ-5D-5L Thermometer Scores at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Bone Biomarker: Serum 25-hydroxyvitamin D at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Renal Biomarker- Serum Cystatin C at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Renal Biomarker- Serum Creatinine at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Renal Biomarker- Serum Creatinine at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Renal Biomarker- Serum Cystatin C at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Renal Biomarker- Serum GFR From Cystatin C Adjusted Using CKD-EPI and Serum GFR From Creatinine Adjusted Using CKD-EPI at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in EQ-5D-5L Utility Score at Weeks 96 and 144(Baseline (Day 1) and at Weeks 96 and 144)
  • Change From Baseline in Renal Biomarker- Serum GFR From Cystatin C Adjusted Using CKD-EPI and Serum GFR From Creatinine Adjusted Using CKD-EPI at Weeks 24 and 48(Baseline (Day 1) and at Weeks 24 and 48)
  • Change From Baseline in Renal Biomarker- Serum GFR From Cystatin C Adjusted Using CKD-EPI and Serum GFR From Creatinine Adjusted Using CKD-EPI at Weeks 24 and 48 in Participants Randomized to TBR Arm Receiving TDF-based Regimen(Baseline (Day 1) and at Weeks 24 and 48)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (1)

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