Efficacy and Safety of Early Switching to Dolutegravir/Lamivudine (DTG/3TC) From INSTI-based Three-drug Regimens in HIV-1-infected Adults Previously naïve Who Achieve Virological Suppression
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 440
- 试验地点
- 23
- 主要终点
- Non-inferior efficacy of switching
研究概览
简要总结
Phase III, randomized, open-label, multicentre, active-controlled, non-inferiority study evaluating the efficacy and safety of early switching to dolutegravir/lamivudine (DTG/3TC) in single-pill, in HIV-1 infected individuals currently taking an INSTI-based three-drug first-line regimen for less than 18 months and who have been virologically suppressed with HIV-1 RNA <50 copies/mL
详细描述
The target population of this study is HIV-1-infected adults without previous virological failure, currently receiving any first-line, triple-drug ART having an INSTI (EVG/cobi, RAL QD, DTG, BIC) as anchor drug associated to any of the following dual NRTI backbone (ABC/3TC, TDF/FTC or TAF/FTC) with virological suppression (HIV-1 RNA < 50 copies/mL).
Participants will be randomly allocated 1:1 to switch to DTG/3TC 50/300 mg as a single pill qd until week 96 (Arm A, early switch) or to continue their INSTI-based ART triple regimen received at screening (Arm B, delayed switch) until week 52, when participants in Arm B with HIV-1 RNA< 50 cp/mL at week 48 will switch to DTG/3TC 50/300 mg qd as a single pill until week 100.
The drugs of both arms will be administered in an open-label manner throughout the entire duration of the study.
The primary analysis will take place after the last participant completes 52 weeks on therapy, to allow for the collection of a confirmatory viral load measurement in participants possibly presenting with HIV-1 RNA ≥50 cp/mL at the Week 48 visit.
If the second determination of HIV-1 RNA is <50 cp/mL, then the participant has not a virological rebound and will be considered eligible to switch to DTG/3TC at Week 52.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 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 documented infection;
- •Aged 18 years or older at the time of signing the informed consent;
- •Stable INSTI-based first-line three-drug ART (switch between different NRTIs are allowed; e.g. from TDF/FTC to TAF/FTC or ABC/3TC, from TAF/FTC to TDF/FTC or ABC/3TC, from ABC/3TC to TAF/FTC or TDF/FTC). Any change of INSTI will not be allowed. Only the following regimens will be allowed:
- •RAL 1200 mg QD plus TDF/FTC or TAF/FTC;
- •RAL 1200 mg QD plus ABC/3TC;
- •EVG/COBI/FTC/TDF or EVG/COBI/FTC/TAF;
- •DTG plus TDF/FTC or TAF/FTC;
- •DTG/ABC/3TC or DTG plus ABC/3TC;
- •BIC/TAF/FTC
- •Previous INSTI-based first-line ART lasting less than 18 months before screening;
- •To have reached a HIV-1 RNA <50 copies/mL during INSTI first-line therapy for less than 12 months. At least a single HIV-1 RNA determination below the threshold within the 6 months before enrollment is required (if a following determination in present, this should not be ≥50 copies (cp)/mL)
- •HIV-1 RNA below 50 copies/mL at the screening visit;
- •No known allergy or intolerance to the study drugs or their components or drugs of their class;
- •A female person is eligible to enter the study if it is confirmed that she is:
- •Not pregnant confirmed by a negative serum pregnancy test at both Screening and Day1;
- •Not breastfeeding;
- •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;
- •Of childbearing potential and agrees to utilize the protocol specified method of contraception (as defined in Appendix 1 -Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential) or be non-heterosexually active or practice sexual abstinence (defined as complete abstinence from penile-vaginal intercourse; periodic abstinence, e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception) from screening throughout the duration of study treatment and for at least two weeks following discontinuation of study drugs;
- •Being able to comply with the protocol requirements and restrictions;
- •Signature of written Informed Consent Form (participants or legal guardian) before that any protocol-specified assessments are conducted.
排除标准
- •A person will be considered not eligible for inclusion in this study if any of the following criteria apply:
- •Having failed virologically;
- •Having changed the INSTI drug;
- •Any major INSTI- or NRTI-resistance-associated mutation documented before starting ART;
- •Women who are pregnant or breastfeeding or plan to become pregnant or breastfeed during the study;
- •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, possibly, HBV DNA as follows:
- •Individuals positive for HBsAg are excluded;
- •Individuals negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded;
- •HCV-RNA positivity needing for any hepatitis C virus (HCV) therapy during the study;
- •Ongoing malignancy other than cutaneous Kaposi's sarcoma (not requiring systemic therapy), basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia;
- •Active opportunistic infections requiring active treatment;
- •Creatinine clearance of <50 mL/min/1.73m2 via CKD-EPI method;
- •Individuals with severe hepatic impairment (Child Pugh class C) and/or unstable liver disease;
- •Any verified Grade 4 laboratory abnormality at screening assessment;
- •Alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) or ALT >3xULN and bilirubin >1.5xULN (with >35% direct bilirubin) at screening assessment;
- •Receipt of investigational research agents within 30 days prior to study entry;
- •Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening;
- •Receipt of immunosuppressive medications or immune-modulators within the past 6 months;
- •Individuals who in the investigator's judgment, poses a significant suicidality risk or with diagnosed major depression, Bipolar Disorders and Psychoses
- •A life expectancy estimated as less than 2 years.
研究组 & 干预措施
ARM A
Participants in Arm A will be randomized to switch to DTG/3TC 50/300 mg QD until week 48 (early switch).
干预措施: DOVATO (Drug)
ARM B
Participants in Arm B will continue the INSTI-based ART regimen until week 48, and then will be switched to DTG/3TC through week 96 (delayed switch).
干预措施: DOVATO (Drug)
结局指标
主要结局
Non-inferior efficacy of switching
时间窗: 48 weeks
Proportion of participants with virological rebound (viral load ≥50 copies/mL or premature discontinuations, irrespective of reason, with last viral load ≥50 copies/mL) at week 48
次要结局
- RT and INSTI resistance-associated mutations(100 weeks)
- Effects of the two strategies on Lipidic profile(96 weeks)
- Efficacy of switching(48 weeks)
- Safety and tolerability(100 weeks)
- Immunologic response and dysfunction(100 weeks)
- Emergent drug resistance-associated mutations(100 weeks)
- Adherence levels to ARVs(96 weeks)
- Evaluate neuropsychiatric symptoms.(96 weeks)