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HIV InfectionsPhase 2ARTISTNCT03991013

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

A Phase 2 study testing Dolutegravir 50 mg in people with HIV Infections, run by University of Cape Town at 1 site in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
HIV Infections
What is being tested?
Dolutegravir 50 mg
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
192 participants
Where
1 siteSouth Africa
Study dates
8 Aug 2019to 27 Oct 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).

Who cannot join

  • 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
Show all 13Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

South Africa1 site
  • Khayelitsha Site B/Ubuntu Community Health Clinic

    Cape Town, Western Cape, 8001

Other trials in South Africa

About this study

Official title: AntiRetroviral Therapy In Second-line: Investigating Tenofovir-lamivudine-dolutegravir (ARTIST): 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-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.

Read more

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
Being tested
Dolutegravir 50 mg, Placebo
Keywords
second line antiretroviral therapy, dolutegravir
Medical subject headings
HIV Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Dolutegravir 50 mgDrug

    Also called Dalimune 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).

  • PlaceboDrug

    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).

Study groups in NCT03991013
Study groupRoleWhat they receive
Supplementary doseActive comparatorTenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days.
Receives: Drug: Dolutegravir 50 mg
Placebo dosePlacebo comparatorTenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 24 weeks

Secondary outcomes (8)
  1. Virological Suppression at 24 Weeks (Sensitivity Analysis)

    Proportion of participants with HIV viral load <50 copies/mL at 24 weeks using pre-specified sensitivity analyses

    Measured: 24 weeks

  2. Virological Suppression at 12 Weeks (Modified ITT)

    Proportion of participants with HIV viral load <50 copies/mL at 12 weeks analysed by modified ITT.

    Measured: 12 weeks

  3. Antiretroviral Resistance Mutations by Genotypic Resistance Testing

    To describe dolutegravir resistance or emergent resistance mutations to tenofovir or lamivudine in participants eligible for genotypic resistance testing by 24 weeks

    Measured: 24 weeks

  4. CD4 Change at 24 Weeks

    Change in CD4 count from screening to week 24

    Measured: 24 weeks

  5. Adverse Events

    To describe grade 3 or 4 adverse events and serious adverse events

    Measured: 24 weeks

  6. All-cause Mortality

    To describe all-cause mortality.

    Measured: 24 weeks

  7. Adherence to Treatment

    To describe tenofovir-diphosphate (TFV-DP) concentrations (ng/mL) at 24 weeks

    Measured: 24 weeks

  8. Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28

    To evaluate the geometric mean ratio (GMR) of dolutegravir trough concentrations on day 7 versus day 28

    Measured: First 28 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Jun 2019
  2. Study start8 Aug 2019
  3. Primary completion26 Apr 2022
  4. Study completion27 Oct 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
192 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03991013
Sponsor's protocol ID
ARTIST
Acronym
ARTIST
Status last verified
Sep 2024
First submitted
31 May 2019
Last updated
1 Oct 2024
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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).

Publications

  • 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.

    PubMed 38372621
  • 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.

    PubMed 36706364
  • 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.

    PubMed 36645792
  • 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.

    PubMed 36017341

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Dolutegravir 50 mg in people with HIV Infections, run by University of Cape Town at 1 site in South Africa.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Aug 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Virological Suppression at 24 Weeks (time frame: 24 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03991013, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Oct 2024.

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