SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03991013

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Zidovudine, Lamivudine and Dolutegravir (AXD) Relative to Tenofovir, Lamivudine and Dolutegravir (TXD) In Second Line Antiretroviral Therapy (ARTIST) Trial: a Randomised Controlled Trial

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 and 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 and dolutegravir, in terms of cost, tolerability and monitoring requirements. The ARTIST study will be a randomised, open-label, active-controlled trial with 48 weeks of follow up, and will evaluate the viral load suppression achieved by participants taking the fixed dose combination of tenofovir, lamivudine and dolutegravir or zidovudine, lamivudine and dolutegravir as second-line therapy. 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 that includes a tenofovir and lamivudine or emtricitabine backbone and a non-nucleoside reverse transcriptase inhibitor (NNRTI). The trial will comprise two stages: the first will evaluate the viral suppression in 65 participants produced by the fixed dose combination of tenofovir, lamivudine and dolutegravir with a supplementary dose of dolutegravir for the first 14 days to mitigate the NNRTI effect in reducing dolutegravir concentrations when switching antiretrovirals. The study will progress to the second stage if this proves effective, and 130 participants will then be randomised to receive the fixed dose combination of tenofovir, lamivudine and dolutegravir (without a supplementary dose of dolutegravir) or the WHO standard of care second-line regimen of zidovudine, lamivudine and dolutegravir. The primary endpoint is viral suppression (viral load<50 copies/mL) at 24 weeks. A Pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and in 12 patients in stage 2 who are randomised to the intervention arm, 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.

NCT03991013 HIV Infections
MeSH: HIV Infections

2 Interventions

Name: TLD: fixed dose combination of tenofovir, lamivudine and dolutegravir antiretroviral therapy

Description: TLD fixed dose combination contains tenofovir 300mg, lamivudine 300mg and dolutegravir 50mg, administered once daily orally for 48 weeks

Type: Drug

TLD

Name: ALD: combination of zidovudine, lamivudine and dolutegravir antiretroviral therapy

Description: ALD is the World Health organization standard of care second line regimen, and contains a combination of zidovudine 300mg and lamivudine 150mg, administered orally as a fixed dose combination twice daily, and dolutegravir 50mg administered orally once daily, for 48 weeks.

Type: Drug

ALD


Primary Outcomes

Description: VL< 50 copies/mL in the participants overall and stratified by presence or absence of resistance mutations at baseline, in stage 1

Measure: Virological suppression in stage 1

Time: 24 weeks

Description: VL< 50 copies/mL in the participants overall and stratified by presence or absence of resistance mutations at baseline, in stage 2

Measure: Virological suppression in stage 2

Time: 24 weeks

Secondary Outcomes

Description: To determine the proportion of patients who develop dolutegravir resistance mutations and new nucleoside reverse transcriptase inhibitors on second-line treatment

Measure: Proportion new ARV resistance

Time: 48 weeks

Description: To evaluate the trough concentrations (ng/mL) of dolutegravir in the period after switching regimens

Measure: PK trough DTG

Time: first 28 days

Description: To evaluate the residual concentrations (ng/mL) of efavirenz in the period after switching regimens

Measure: PK residual EFV

Time: first 28 days

Description: To evaluate the proportion of patients with dolutegravir trough concentrations above the PA-IC90 value at all PK time points.

Measure: PK DTG above PA-IC90

Time: first 28 days

Description: To describe tenofovir-diphosphate concentration (ng/mL - marker of adherence) in those with virological failure at 24 and 48 weeks by treatment arm and to compare to a group of matched controls.

Measure: Adherence in failures stage 1

Time: 24 and 48 weeks

Description: To describe dolutegravir concentration (ng/mL - marker of adherence) in those with virological failure at 24 and 48 weeks by treatment arm and to compare to a group of matched controls.

Measure: Adherence in failures stage 2

Time: 24 and 48 weeks

Description: To describe adverse events among the study cohort in stage one and in stage two by treatment arm

Measure: Description of adverse events

Time: 48 weeks

Description: To describe all-cause mortality among the study cohort in stage one and in stage two by treatment arm

Measure: Description of all cause mortality

Time: 48 weeks

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There are 2 SNPs

SNPs


1 K65R

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 that includes a tenofovir and lamivudine or emtricitabine backbone and a non-nucleoside reverse transcriptase inhibitor (NNRTI). --- K65R ---


2 M184V

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 that includes a tenofovir and lamivudine or emtricitabine backbone and a non-nucleoside reverse transcriptase inhibitor (NNRTI). --- K65R --- --- M184V ---



HPO Nodes