Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial (ARTIST)
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|ClinicalTrials.gov Identifier: NCT03991013|
Recruitment Status : Recruiting
First Posted : June 19, 2019
Last Update Posted : August 5, 2020
The strategy to support virological suppression on second-line antiretroviral treatment (ART) includes the provision of ART that has a low pill burden, good tolerability, low toxicity, is easily monitored, has a high barrier to resistance, and that is low cost. The fixed-dose combination of tenofovir-lamivudine-dolutegravir offers significant advantage as a potential second-line regimen compared to the World Health Organization standard of care second-line regimen of zidovudine-lamivudine-dolutegravir, in terms of cost, tolerability and monitoring requirements.
The ARTIST study is a phase 2, randomised, double-blind, placebo-controlled trial aiming to determine the proportion of patients achieving virological suppression when recycling the tenofovir-emtricitabine/lamivudine backbone with dolutegravir (tenofovir-lamivudine-dolutegravir fixed-dose combination) as a second-line with and without a lead-in supplementary dose of dolutegravir, in patients failing a tenofovir-emtricitabine/lamivudine-efavirenz first-line regimen.
There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. The strategy of giving a lead-in supplementary dose of dolutegravir is in view of the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks after efavirenz is stopped; the inducing effect decreases with time after efavirenz is stopped.
Given that these patients will have elevated viral loads, a high baseline risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance and efavirenz resistance, and the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks, this study will comprise two stages. The first stage will evaluate virological suppression in 62 participants initiated on the fixed-dose combination of tenofovir-lamivudine-dolutegravir with a lead-in supplementary dose of dolutegravir for the first 14 days. The study will progress to the second stage if this strategy proves effective, and 130 participants will then be randomised to receive the fixed-dose combination of tenofovir-lamivudine-dolutegravir with and without this lead-in dose.
The primary endpoint is virological suppression (viral load <50 copies/mL) at 24 weeks.
A pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and 24 participants in stage 2, to assess the trough concentrations of dolutegravir and off-treatment concentrations of efavirenz at day 3, 7, 14, and 28. This is to evaluate the need for the lead-in supplementary dose of dolutegravir.
|Condition or disease||Intervention/treatment||Phase|
|HIV Infections||Drug: Dolutegravir 50 mg Drug: Placebo||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||192 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||This study will be a phase 2, randomised, double-blind, placebo-controlled trial of tenofovir-lamivudine-dolutegravir fixed-dose combination daily with a lead-in supplementary 50 mg dose of dolutegravir versus matching placebo taken 12 hours later for the first 14 days in patients failing a first-line tenofovir-emtricitabine/lamivudine-efavirenz regimen.|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||AntiRetroviral Therapy In Second-line: Investigating Tenofovir-lamivudine-dolutegravir (ARTIST): a Randomised Controlled Trial|
|Actual Study Start Date :||August 8, 2019|
|Estimated Primary Completion Date :||December 31, 2020|
|Estimated Study Completion Date :||June 30, 2021|
Active Comparator: Supplementary dose
Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days.
Drug: Dolutegravir 50 mg
Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks).
Other Name: Dalimune 50 mg
Placebo Comparator: Placebo dose
Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days.
Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks).
- Virological suppression at 24 weeks [ Time Frame: 24 weeks ]Proportion of participants with HIV viral load <50 copies/mL at 24 weeks analysed by modified intention to treat (ITT) and according to the FDA snapshot algorithm, overall and stratified by the presence or absence of resistance to tenofovir and lamivudine at baseline.
- Antiretroviral resistance mutations by genotypic resistance testing [ Time Frame: Baseline, 24 and 48 weeks ]To describe resistance profile at baseline (NRTI and efavirenz resistance), and treatment-emergent resistance to integrase inhibitor and NRTI in participants who experience virological failure.
- Residual efavirenz concentrations and dolutegravir trough concentrations [ Time Frame: First 28 days ]To evaluate the trough concentrations (ng/mL) of dolutegravir and the residual concentrations (ng/mL) of efavirenz in the period after switching regimens. To evaluate the proportion of participants with dolutegravir trough concentrations above the protein-adjusted 90% inhibitory concentration (PA-IC90) value at all pharmacokinetics time points.
- Virological suppression at 12 and 48 weeks (modified ITT) [ Time Frame: 12 and 48 weeks ]Proportion of participants with HIV viral load <50 copies/mL at 12 and 48 weeks analysed by modified ITT.
- Virological suppression at 12, 24 and 48 weeks (per protocol) [ Time Frame: 12, 24 and 48 weeks ]Proportion of participants with HIV viral load <50 copies/mL at 12, 24 and 48 weeks analysed per protocol.
- Adherence to treatment [ Time Frame: 24 and 48 weeks ]To describe tenofovir-diphosphate concentration (ng/mL) in participants who experience virological failure and matched controls from among those who are suppressed at 24 and 48 weeks.
- CD4 change at 24 and 48 weeks [ Time Frame: 24 and 48 weeks ]Change in CD4 count from screening at week 24 and 48.
- Adverse events [ Time Frame: 48 weeks ]To describe grade 3 and 4 drug-related adverse events, serious adverse events, and any adverse event requiring discontinuation of any drug in the ART regimen.
- All-cause mortality [ Time Frame: 48 weeks ]To describe all-cause mortality.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03991013
|Contact: Graeme Meintjes, PhDfirstname.lastname@example.org|
|Contact: Claire Keeneemail@example.com|
|Khayelitsha Site B/Ubuntu Community Health Clinic||Recruiting|
|Cape Town, Western Cape, South Africa, 8001|
|Contact: Ying Zhao, MMed +27738159538 firstname.lastname@example.org|
|Principal Investigator: Graeme Meintjes, PhD|
|Sub-Investigator: Ying Zhao, MMed|
|Principal Investigator:||Graeme Meintjes, PhD||University of Cape Town|
|Principal Investigator:||Claire Keene||Médecins Sans Frontières, Belgium|