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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
Sponsor:
Collaborators:
Wellcome Trust
Médecins Sans Frontières, Belgium
Information provided by (Responsible Party):
Graeme Meintjes, University of Cape Town

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

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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


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).




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.



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

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


Contacts
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Contact: Graeme Meintjes, PhD +27214066075 graeme.meintjes@uct.ac.za
Contact: Claire Keene +27663477892 msfocb-khayelitsha-hivmam@brussels.msf.org

Locations
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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
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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

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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    Key Record Dates
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).

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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:
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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