Nucleosides And Darunavir/Dolutegravir In Africa (NADIA): a Randomised Controlled Trial of Darunavir Versus Dolutegravir and Tenofovir Versus Zidovudine in Second-line Antiretroviral Therapy Regimens for the Public Health Approach in Sub-Saharan Africa
试验速览
- 阶段
- 3 期
- 入组人数
- 465
- 试验地点
- 1
- 主要终点
- Plasma viral load < 400 copies/ml at 48 weeks
研究概览
简要总结
This trial evaluates options for second-line antiretroviral therapy in patients failing on a non-nucleoside reverse transcriptase inhibitor (NNRTI) and tenofovir (TDF)-based first-line regimen in the setting of the public health approach in sub-Saharan Africa (with assumed substantial nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance). The trial tests two hypotheses. Firstly that a regimen of dolutegravir (DTG) with two NRTIs is non-inferior to a regimen of ritonavir-boosted darunavir (DRV/r) with two NRTIs. Secondly that continuing an NRTI regimen of TDF and lamivudine (3TC) is non-inferior to switching to zidovudine (ZDV) and 3TC.
The trial is a parallel group, open-label, multi-centre, factorial (2X2) randomised, controlled trial. Patients will be randomised to either DTG or DRV/r with a second randomisation to ZDV and 3TC or TDF and 3TC. Treatment efficacy will be monitored by testing viral load (VL). Analyses will compare DRV/r with DTG; and ZDV/3TC with TDF/3TC by intention to treat analysis on the primary outcome parameter of plasma VL below 400 copies/ml at 48 weeks. Trial follow-up will continue to 96 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, age 12 years and above
- •Body weight at least 40kg
- •Taking a tenofovir plus lamivudine/emtricitabine plus NNRTI-based regimen continuously for a total period of at least 6 months
- •Good adherence to ART, defined as missing medication on no more than 3 days in the one month prior to screening. [Patients who do not have good adherence should be given adherence counselling and re-assessed after an interval of not less than 4 weeks].
- •HIV treatment failure defined by virological criteria (modified from WHO 2016 criteria); Viral load ≥ 1000 copies/ml at screening AND EITHER Viral load ≥ 1000 copies/ml on the previous test, taken after at least 6 months on ART, and at no more than 6 months prior to screening and at no less than 4 weeks prior to screening, with adherence counselling given after the previous test OR Viral load ≥ 1000 copies/ml on a confirmatory test taken no less than 4 weeks after screening with adherence counselling given after the screening test
- •If a woman of childbearing potential, must be willing to use effective contraception. [Childbearing potential is defined as being not premenarchal; not post-menopausal (> 12 months of spontaneous amenorrhea and ≥45 years of age); and not permanently sterilised].
- •Willing and able to provide written informed consent
- •Able to attend regular study follow-up visits
排除标准
- •Prior use of protease inhibitor or integrase inhibitor therapy
- •Requirement for concomitant medication with known major interactions with study drugs for which drug substitutions or dose alterations are not available or acceptable (if the patient requires rifamycin-based TB treatment, rifabutin must be available at the site).
- •Women who are currently pregnant or breastfeeding.
- •Severe hepatic impairment (with ascites and/or encephalopathy)
- •ALT > 5 times upper limit of normal
- •Estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73m2 at screening calculated using the CKD-EPI equation
- •Current participation in another clinical trial or research protocol (may be permitted in some circumstances; but must first be discussed with the NADIA Chief Investigator)
- •Life expectancy of less than one month in the opinion of the treating physician
研究组 & 干预措施
Dolutegravir Tenofovir Lamivudine
Dolutegravir 50mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
干预措施: Lamivudine (Drug)
Darunavir/r Zidovudine Lamivudine
Darunavir 800mg once daily Ritonavir 100mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
干预措施: Darunavir (Drug)
Darunavir/r Zidovudine Lamivudine
Darunavir 800mg once daily Ritonavir 100mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
干预措施: Ritonavir (Drug)
Darunavir/r Zidovudine Lamivudine
Darunavir 800mg once daily Ritonavir 100mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
干预措施: Zidovudine (Drug)
Darunavir/r Zidovudine Lamivudine
Darunavir 800mg once daily Ritonavir 100mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
干预措施: Lamivudine (Drug)
Darunavir/r Tenofovir Lamivudine
Darunavir 800mg once daily Ritonavir 100mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
干预措施: Darunavir (Drug)
Darunavir/r Tenofovir Lamivudine
Darunavir 800mg once daily Ritonavir 100mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
干预措施: Ritonavir (Drug)
Darunavir/r Tenofovir Lamivudine
Darunavir 800mg once daily Ritonavir 100mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
干预措施: Tenofovir (Drug)
Darunavir/r Tenofovir Lamivudine
Darunavir 800mg once daily Ritonavir 100mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
干预措施: Lamivudine (Drug)
Dolutegravir Zidovudine Lamivudine
Dolutegravir 50mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
干预措施: Dolutegravir (Drug)
Dolutegravir Zidovudine Lamivudine
Dolutegravir 50mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
干预措施: Zidovudine (Drug)
Dolutegravir Zidovudine Lamivudine
Dolutegravir 50mg once daily Zidovudine 300mg twice daily Lamivudine 150mg twice daily Combination given for 96 weeks
干预措施: Lamivudine (Drug)
Dolutegravir Tenofovir Lamivudine
Dolutegravir 50mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
干预措施: Dolutegravir (Drug)
Dolutegravir Tenofovir Lamivudine
Dolutegravir 50mg once daily Tenofovir 300mg once daily Lamivudine 300mg once daily Combination given for 96 weeks
干预措施: Tenofovir (Drug)
结局指标
主要结局
Plasma viral load < 400 copies/ml at 48 weeks
时间窗: 48 weeks
次要结局
- Incident (new or recurrent) WHO stage 4 event(48 and 96 weeks)
- Incident serious non-AIDS event(48 and 96 weeks)
- Death(48 and 96 weeks)
- Time to new or recurrent WHO Stage 4 event, serious non-AIDS event, or death(96 weeks)
- Grade 3 or 4 clinical adverse events(48 and 96 weeks)
- Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to DRV or DTG(48 and 96 weeks)
- Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to both zidovudine and tenofovir(48 and 96 weeks)
- CD4+ cell count change from baseline(48 and 96 weeks)
- Plasma viral load < 50 copies/ml(48 and 96 weeks)
- Plasma viral load rebound (≥ 1000 copies/ml, confirmed)(48 and 96 weeks)
- Plasma viral load < 1000 copies/ml(48 and 96 weeks)
- Plasma viral load < 400 copies/ml at 96 weeks(96 weeks)
- Plasma viral load rebound (≥ 400 copies/ml, confirmed)(48 and 96 weeks)
- Plasma viral load rebound (≥ 50 copies/ml, confirmed)(48 and 96 weeks)
- Viral load rebound (≥ 1000 copies/ml, confirmed) with ≥ 1 major resistance mutation (IAS list) to DRV or DTG(48 and 96 weeks)
- Grade 3 or 4 clinical adverse events (possibly, probably or definitely related to ART)(48 and 96 weeks)
- Serious Adverse Events(48 and 96 weeks)