Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial (ARTIST)

• ClinicalTrials.gov Identifier: NCT03991013
• Recruitment Status: Recruiting
• First Posted: June 19, 2019
• Last Update Posted: August 5, 2020
• Sponsor: University of Cape Town
• Collaborators: Wellcome Trust; Médecins Sans Frontières, Belgium
• Information provided by (Responsible Party): Graeme Meintjes, University of Cape Town

Study Description

Brief Summary:

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 192 participants
• Allocation: Randomized
• 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)
• Primary Purpose: Treatment
• 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

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Placebo; 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).

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. CD4 change at 24 and 48 weeks [ Time Frame: 24 and 48 weeks ]
   Change in CD4 count from screening at week 24 and 48.
7. 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.
8. All-cause mortality [ Time Frame: 48 weeks ]
   To describe all-cause mortality.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

HIV positive patients over 18 years old, who have failed first-line ART regimen of tenofovir-emtricitabine/lamivudine-efavirenz, 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 viral load (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 VLs 2-3 months apart: >2 log drop in VLs 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
• Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula
• Alanine aminotransferase >100 U/L 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 dolutegravir and thus requires dose adjustments
• Any 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 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

Contact: Graeme Meintjes, PhD; +27214066075; graeme.meintjes@uct.ac.za

Contact: Claire Keene; +27663477892; msfocb-khayelitsha-hivmam@brussels.msf.org

Locations

South Africa

Khayelitsha Site B/Ubuntu Community Health Clinic; Recruiting

Cape Town, Western Cape, South Africa, 8001

Contact: Ying Zhao, MMed +27738159538 zhxyin001@myuct.ac.za

Principal Investigator: Graeme Meintjes, PhD

Sub-Investigator: Ying Zhao, MMed

Sponsors and Collaborators

University of Cape Town

Wellcome Trust

Médecins Sans Frontières, Belgium

Investigators

• Principal Investigator: Graeme Meintjes, PhD; University of Cape Town
• Principal Investigator: Claire Keene; Médecins Sans Frontières, Belgium

  Study Documents (Full-Text)

Documents provided by Graeme Meintjes, University of Cape Town:

Statistical Analysis Plan  [PDF] December 19, 2019

Study Protocol  [PDF] June 17, 2020

Informed Consent Form  [PDF] June 17, 2020

More Information

• Responsible Party: Graeme Meintjes, Professor of Medicine, University of Cape Town (UCT), University of Cape Town
• ClinicalTrials.gov Identifier: NCT03991013
• Other Study ID Numbers: ARTIST
• First Posted: June 19, 2019
• Last Update Posted: August 5, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data will be shared with other organisations or individuals for further research upon a reasonable request to the University of Cape Town PI, provided that certain conditions are met (including but not limited to the ethical standards upheld by Human Research Ethics Committee (HREC) that approved the initial study).
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: From the time the final results are published
• Access Criteria: Data will be shared with other organisations or individuals for further research upon a reasonable request to the University of Cape Town PI, provided that certain conditions are met (including but not limited to the ethical standards upheld by HREC that approved the initial study).

• 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; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Dolutegravir; HIV Integrase Inhibitors; Integrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents