Clinical Trials

MainTitle

Tenofovir/Lamivudine/Dolutegravir Combination as Second Line ART: a Randomised Controlled Trial (ARTIST) (ARTIST)

This study is currently recruiting participants. (see Contacts and Locations)

Verified August 2019 by Graeme Meintjes, University of Cape Town

Sponsor
University of Cape Town

Collaborator
Médecins Sans Frontières, Belgium

Information provided by (Responsible Party)
Graeme Meintjes, University of Cape Town

ClinicalTrials.gov Identifier
NCT03991013

First received: May 31, 2019
Last updated: August 15, 2019
Last Verified: August 2019
History of Changes
Purpose

Purpose

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.

Condition Intervention Phase
HIV Infections

Drug : TLD: fixed dose combination of tenofovir, lamivudine and dolutegravir antiretroviral therapy
Drug : ALD: combination of zidovudine, lamivudine and dolutegravir antiretroviral therapy
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study will be a randomised, open-label, active-controlled trial to determine the proportion of patients achieving viral suppression on tenofovir/lamivudine/dolutegravir and zidovudine/lamivudine/dolutegravir as second line. Given that these patients will all have elevated viral loads and a high baseline risk of NRTI resistance, and the inducing effect of efavirenz on dolutegravir metabolism (persisting after efavirenz is stopped), we propose two stages: Stage 1: patients will be initiated on fixed dose tenofovir/lamivudine/dolutegravir (supplemented with 50mg dolutegravir daily for the first 14 days) Stage 2: will describe the VL suppression in the intervention and control arms, but will not be powered for a formal non-inferiority comparison Intervention arm: patients will be initiated on fixed dose tenofovir/lamivudine/dolutegravir (no supplementary dolutegravir) Control arm: patients initiated on zidovudine and lamivudine twice daily, with dolutegravir once daily
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Zidovudine, Lamivudine and Dolutegravir (AXD) Relative to Tenofovir, Lamivudine and Dolutegravir (TXD) In Second Line Antiretroviral Therapy (ARTIST) Trial: a Randomised Controlled Trial

Further study details as provided by Graeme Meintjes, University of Cape Town:

Primary Outcome Measures

  • Virological suppression in stage 1 [ Time Frame: 24 weeks ]
    VL< 50 copies/mL in the participants overall and stratified by presence or absence of resistance mutations at baseline, in stage 1
  • Virological suppression in stage 2 [ Time Frame: 24 weeks ]
    VL< 50 copies/mL in the participants overall and stratified by presence or absence of resistance mutations at baseline, in stage 2
Secondary Outcome Measures:
  • Proportion new ARV resistance [ Time Frame: 48 weeks ]
    To determine the proportion of patients who develop dolutegravir resistance mutations and new nucleoside reverse transcriptase inhibitors on second-line treatment
  • PK trough DTG [ Time Frame: first 28 days ]
    To evaluate the trough concentrations (ng/mL) of dolutegravir in the period after switching regimens
  • PK residual EFV [ Time Frame: first 28 days ]
    To evaluate the residual concentrations (ng/mL) of efavirenz in the period after switching regimens
  • PK DTG above PA-IC90 [ Time Frame: first 28 days ]
    To evaluate the proportion of patients with dolutegravir trough concentrations above the PA-IC90 value at all PK time points.
  • Adherence in failures stage 1 [ Time Frame: 24 and 48 weeks ]
    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.
  • Adherence in failures stage 2 [ Time Frame: 24 and 48 weeks ]
    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.
  • Description of adverse events [ Time Frame: 48 weeks ]
    To describe adverse events among the study cohort in stage one and in stage two by treatment arm
  • Description of all cause mortality [ Time Frame: 48 weeks ]
    To describe all-cause mortality among the study cohort in stage one and in stage two by treatment arm

Estimated Enrollment: 195
Study Start Date: July 1, 2019
Estimated Study Completion Date: June 30, 2021
Estimated Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: TLD
65 participants
Drug: TLD: fixed dose combination of tenofovir, lamivudine and dolutegravir antiretroviral therapy

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

Active Comparator: ALD
65 participants
Drug: ALD: combination of zidovudine, lamivudine and dolutegravir antiretroviral therapy

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.

Eligibility

Eligibility

Ages Eligible for Study: 18 Years and older  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:
HIV positive patients over 18 years old, who have failed their first-line ART regimen, are able to attend the study clinic for one year of scheduled visits and who have given written, informed consent will be enrolled in this study. In female patients of child-bearing potential, those willing to use effective and reliable contraception for the duration of the study will be eligible
Failure of a first-line regimen is defined as:
• A VL of >1000 copies/ml (within the previous two months) and an immediately prior VL >1000 copies/ml, taken 2-24 months prior (based on data captured by National Health Laboratory Service)

Exclusion Criteria:

    • If the patient has two VL 2-3 months apart: > 2 log drop in VL between the most recent VL (within the previous two months) and the immediately prior VL (taken 2-3 months prior)
    • CD4 count < 100 cells/microlitre
    • Renal impairment (estimated Cr Cl < 50ml/min using the MDRD formula)
    • Haemoglobin < 7.5
    • ALT > 100 or total bilirubin > twice the upper limit of normal
    • Pregnant or desire to become pregnant during the study period (48 weeks)
    • Breastfeeding
    • Being treated for active tuberculosis (TB) or concern that patient has undiagnosed active TB (based on symptom screening) as rifampicin reduces the concentrations of DTG and thus requires dose adjustments
    • Any previous or current diagnosis of malignancy
    • Allergy or intolerance to one of the drugs in regimen
    • Active, severe psychiatric disease judged likely to impact adherence
    • Current substance abuse judged to be likely to impact adherence On treatment for AIDS-defining condition (not including secondary prophylaxis maintenance therapy)
    • Any other clinical condition that in the opinion of an investigator puts the patient
    at increased risk if participating in the study.

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03991013

Contacts

Contact:   Claire M Keene +27829580556 msfocb-khayelitsha-hivmam@brussels.msf.org
Contact:   Graeme Meintjes graeme.meintjes@uct.ac.za

Locations

South Africa
Site B Khayelitsha Community Health Clinic Recruiting
Cape Town, Western Cape, South Africa
Contact: Claire M Keene, MBBCh    msfocb-khayelitsha-hivmam@brussels.msf.org

Sponsors and Collaborators

University of Cape Town
Médecins Sans Frontières, Belgium

Investigators

Principal Investigator: Graeme Meintjes University of Cape Town
Principal Investigator: Claire M Keene MSF (Medecins Sans Frontieres) Belgium
More Information

More Information


Responsible Party: Graeme Meintjes, Professor of Medicine, University of Cape Town (UCT), University of Cape Town  
ClinicalTrials.gov Identifier: NCT03991013   History of Changes  
Other Study ID Numbers: ARTIST  
Study First Received: May 31, 2019  
Last Updated: August 15, 2019  
Individual Participant Data    
Plan to Share IPD: Yes  

Studies a U.S. FDA-regulated Drug Product: No  
Studies a U.S. FDA-regulated Device Product: No  
Product Manufactured in and Exported from the U.S.: No  

Keywords provided by Graeme Meintjes, University of Cape Town:

second line antiretroviral therapy
dolutegravir

Additional relevant MeSH terms:
HIV Infections
Tenofovir
Lamivudine
Zidovudine
Dolutegravir
Anti-Retroviral Agents

ClinicalTrials.gov processed this data on October 15, 2019
This information is provided by ClinicalTrials.gov.