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

NCT03991013 | Completed Phase 2 Results

• 1 other identifier: ARTIST
• Study Type: interventional
• Target: 192
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV Infections

Keywords

second line antiretroviral therapy; dolutegravir

Outcome Measures

Primary Outcomes (1)

• Virological Suppression at 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

  24 weeks

Secondary Outcomes (8)

• Virological Suppression at 24 Weeks (Sensitivity Analysis)

  24 weeks

• Virological Suppression at 12 Weeks (Modified ITT)

  12 weeks

• Antiretroviral Resistance Mutations by Genotypic Resistance Testing

  24 weeks

• CD4 Change at 24 Weeks

  24 weeks

• Adverse Events

  24 weeks

Study Arms (2)

Supplementary dose

ACTIVE COMPARATOR

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

Placebo dose

PLACEBO COMPARATOR

Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days.

Drug: Placebo

Interventions

Dolutegravir 50 mg DRUG

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).

Also known as: Dalimune 50 mg

Supplementary dose

Placebo DRUG

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).

Placebo dose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Cape Town: lead
• Wellcome Trust: collaborator
• Médecins Sans Frontières, Belgium: collaborator

Study Sites (1)

Khayelitsha Site B/Ubuntu Community Health Clinic

Cape Town, Western Cape, 8001, South Africa

Location

Related Publications (4)

• Griesel R, Banda CG, Zhao Y, Omar Z, Wiesner L, Meintjes G, Sinxadi P, Maartens G. Pharmacokinetics of Single-Dose Versus Double-Dose Dolutegravir After Switching From a Failing Efavirenz-Based Regimen. J Acquir Immune Defic Syndr. 2024 May 1;96(1):85-91. doi: 10.1097/QAI.0000000000003402.

  PMID: 38372621 DERIVED

• Keene CM, Cassidy T, Zhao Y, Griesel R, Jackson A, Sayed K, Omar Z, Hill A, Ngwenya O, Van Zyl G, Flowers T, Goemaere E, Maartens G, Meintjes G. Recycling Tenofovir in Second-line Antiretroviral Treatment With Dolutegravir: Outcomes and Viral Load Trajectories to 72 weeks. J Acquir Immune Defic Syndr. 2023 Apr 15;92(5):422-429. doi: 10.1097/QAI.0000000000003157.

  PMID: 36706364 DERIVED

• Zhao Y, Griesel R, Omar Z, Simmons B, Hill A, van Zyl G, Keene C, Maartens G, Meintjes G. Initial Supplementary Dose of Dolutegravir in Second-Line Antiretroviral Therapy: A Noncomparative, Double-Blind, Randomized Placebo-Controlled Trial. Clin Infect Dis. 2023 May 24;76(10):1832-1840. doi: 10.1093/cid/ciad023.

  PMID: 36645792 DERIVED

• Zhao Y, Keene C, Griesel R, Sayed K, Gcwabe Z, Jackson A, Ngwenya O, Schutz C, Goliath R, Cassidy T, Goemaere E, Hill A, Maartens G, Meintjes G. AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial. Wellcome Open Res. 2021 Feb 17;6:33. doi: 10.12688/wellcomeopenres.16597.1. eCollection 2021.

  PMID: 36017341 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

dolutegravir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: Prof Graeme Meintjes
• Organization: University of Cape Town

Graeme.Meintjes@uct.ac.za

+27 (0) 21 4066075

Study Officials

• Graeme Meintjes, PhD

  University of Cape Town

  PRINCIPAL INVESTIGATOR

• Claire Keene

  Médecins Sans Frontières, Belgium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine, University of Cape Town (UCT)

Model Details: 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.

Study Record Dates

• First Submitted: May 31, 2019
• First Posted: June 19, 2019
• Study Start: August 8, 2019
• Primary Completion: April 26, 2022
• Study Completion: October 27, 2022
• Last Updated: October 1, 2024
• Results First Posted: August 9, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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).

Locations

ZA (1)