Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis (RADIANT-TB)

November 7, 2022 updated by: Prof Gary Maartens, University of Cape Town

Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis: a Phase 2 Non-comparative Randomised Controlled Trial

The investigators propose to conduct a phase 2 randomised (1:1) double-blind placebo-controlled trial of the dolutegravir-lamivudine-tenofovir fixed dose combination tablet daily with an additional 50 mg dose of dolutegravir/matching placebo taken 12 hours later in ART-naïve or fisrt-line interrupted HIV-infected patients on rifampicin-based anti-tuberculosis therapy. The hypothesis is that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based anti-tuberculosis therapy.

Study Overview

Status

Completed

Detailed Description

Dolutegravir is being rolled out to replace efavirenz in first-line antiretroviral therapy (ART) in low-middle income countries (LMICs) because it is more effective, better tolerated, and has a considerably higher genetic barrier to resistance.

Tuberculosis is the commonest cause of HIV-related morbidity and mortality in LMICs. Rifampicin, which is a key component of anti-tuberculosis therapy, induces genes that are important in the metabolism and transport of dolutegravir. The resulting drug-drug interaction between dolutegravir and rifampicin significantly reduces dolutegravir exposure, which can be overcome by increasing the dose of dolutegravir to 50 mg 12 hourly.

The additional dose of dolutegravir will be difficult to implement in high burden settings. Furthermore, the additional dolutegravir tablet increases pill burden and costs. If standard dose dolutegravir is shown to be effective in patients with tuberculosis this would sweep away one of the major barriers to its implementation in LMICs. There are three lines of evidence to support studying standard dose dolutegravir in patients with HIV-associated tuberculosis.

First, there are compelling pharmacokinetic and pharmacodynamic data supporting the therapeutic efficacy of lower dolutegravir exposure. Second, the investigators have conducted a drug-drug interaction study of dolutegravir dosed at 50 mg or 100 mg once daily in healthy volunteers with rifampicin. Although, as expected, concomitant rifampicin significantly reduced dolutegravir exposure at both doses, all dolutegravir trough concentrations on rifampicin were above the protein-adjusted 90% inhibitory concentration (PA IC90). Third, exposure to the first-generation integrase inhibitor raltegravir is also significantly reduced with concomitant rifampicin. A phase 2 study in patients with HIV-associated tuberculosis showed that virologic outcomes were similar with standard and double dose raltegravir. It is plausible that findings could be similar with dolutegravir.

The hypothesis is that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based anti-tuberculosis therapy. If the proportion of participants who achieve virological suppression on standard dose dolutegravir is acceptable, this would pave the way for a phase 3 trial of dolutegravir 50 mg daily versus an appropriate standard of care regimen, like efavirenz-based ART, in patients with HIV-associated tuberculosis.

Study Type

Interventional

Enrollment (Actual)

108

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Western Cape
      • Cape Town, Western Cape, South Africa, 8001
        • Khayelitsha Site B/Ubuntu Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 108 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • HIV-1 infection as documented by screening plasma HIV-1 RNA >1000 c/mL
  • ART-naïve (short-term antiretroviral use for prevention of mother-to-child transmission will be allowed) or
  • ART treatment interrupters on ART <6 months prior to interruption or virologically suppressed (<50 copies/mL or LDL) <6 months prior to interruption
  • On rifampicin-based therapy for tuberculosis for <3 months
  • CD4 counts >100 cells/µL
  • Women of child-bearing potential willing to use adequate contraception (defined as either an intrauterine contraceptive device or hormonal contraception as per national guidelines)

Exclusion Criteria:

  • Pregnant/breastfeeding
  • Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease (MDRD) study)
  • Alanine aminotransferase >3 times upper limit of normal (ULN)
  • Allergy or intolerance to one of the drugs in regimen
  • Concomitant medication known to significantly reduce or increase dolutegravir exposure (except rifampicin)
  • Active psychiatric disease or substance abuse
  • On treatment for active AIDS-defining condition other than tuberculosis (participants on maintenance therapy may be enrolled)
  • Malignancy
  • Any other clinical condition that in the opinion of an investigator puts the patient at increased risk of participating in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Supplementary dose
Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later.
Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg.
Other Names:
  • Tivicay 50 mg
Placebo Comparator: Placebo dose
Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with placebo taken 12 hours later.
Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is not given with a supplementary dose of dolutegravir 50 mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Virological Suppression at 24 Weeks
Time Frame: 24 weeks
Proportion with HIV viral load <50 copies/mL at 24 weeks analysed by modified intention to treat (ITT), which includes all participants who received at least one dose of dolutegravir, and according to the FDA snapshot algorithm.
24 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Virological Suppression at 12 Weeks (Modified ITT)
Time Frame: 12 weeks
Proportion with HIV viral load <50 copies/mL at 12 weeks analyzed modified ITT.
12 weeks
Virological Suppression at 24 Weeks (Per Protocol)
Time Frame: 24 weeks
Proportion with HIV viral load <50 copies/mL at 24 weeks analyzed per protocol.
24 weeks
Virological Suppression at 48 Weeks (Modified ITT)
Time Frame: 48 weeks
Proportion with HIV viral load <50 copies/mL at 48 weeks analyzed modified ITT.
48 weeks
Virological Suppression at 48 Weeks (Per Protocol)
Time Frame: 48 weeks
Proportion with HIV viral load <50 copies/mL at 48 weeks analyzed per protocol.
48 weeks
CD4 Change at 24 and 48 Weeks
Time Frame: 24 and 48 weeks
Change in CD4 count from screening at week 24 and week 48.
24 and 48 weeks
Dolutegravir Trough Concentrations
Time Frame: 4, 8, 12, 24, and 48 weeks
Proportion with dolutegravir trough concentrations above the PA IC90 at weeks 4, 8, 12, 24, and 48.
4, 8, 12, 24, and 48 weeks
Grade 3 or 4 Adverse Events
Time Frame: 48 weeks
Grade 3 or 4 drug-related adverse events will be accessed throughout the trial.
48 weeks
Change in Sleep Assessment From Baseline
Time Frame: 4, 8, 12, 16, 20, 24, and 48 weeks

Insomnia severity scale - measures sleep patterns and how this influences daily functioning and quality of life (assessed at weeks 4, 8, 12, 16, 20, 24, and 48).

  1. Please rate the current (i.e. last 2 weeks) severity of your insomnia problem(s):

    None, Mild, Moderate, Severe, Very Severe

  2. How satisfied/dissatisfied are you with your current sleep pattern? 0 - 5 (Very Satisfied - Very Dissatisfied)
  3. To what extent do you consider your sleep problem to interfere with your daily functioning? 0 - 4 (Not interfering at all, A little, Somewhat, Much, Interfering very much)
  4. How noticeable to others do you think your sleeping problem is in terms of impairing the quality of your life? 0 - 4 (Not noticeable at all, Barely, Somewhat, Much, Very much noticeable)
  5. How worried/distressed are you about your current sleep problem? 0 - 4 (Not noticeable at all, A little, Somewhat, Much, Very much)
4, 8, 12, 16, 20, 24, and 48 weeks
Change in Mental Health Assessment From Baseline
Time Frame: 12, 24, and 48 weeks
Mental health will be assessed by a questionnaire given at baseline, 12 weeks, 24 weeks, and 48 weeks. The questionnaire is standardized and has been based on the mini international neuropsychiatric interview (version 7.0.0). All questions in the questionnaire require a yes/no answer.
12, 24, and 48 weeks
Serious Adverse Events
Time Frame: 48 weeks
Document any serious adverse events that occur throughout the trial.
48 weeks
Adverse Events Requiring Discontinuation of an ART Drug
Time Frame: 48 weeks
Any adverse event that requires discontinuation of any drug in the ART regimen throughout the trial.
48 weeks
Antiretroviral Resistance Mutations Testing by Genotypic Resistance Assay in Participants With Virologic Failure
Time Frame: 24 and 48 weeks
If a viral load is >1000 copies/mL at week 24 or at week 48, or if the viral load was suppressed and then rebounded to >1000 copies/mL, a sample will be taken for resistance testing. Antiretroviral resistance mutations in participants with virologic failure will be assessed by genotypic resistance assay and compared to stored plasma at baseline to distinguish emergent from pre-treatment resistance.
24 and 48 weeks
Primary Outcome Differences Among ART-naïve Versus First-line Interruption Status
Time Frame: 24 weeks
The primary outcome measure (proportion with HIV viral load <50 copies/mL at 24 weeks analysed by modified intention to treat (ITT), which includes all participants who received at least one dose of dolutegravir, and according to the FDA snapshot algorithm) will be stratified by ART-naïve versus first-line interruption status.
24 weeks
Secondary Outcome Differences Among ART-naïve Versus First-line Interruption Status by Modified ITT Analysis
Time Frame: 12 and 48 weeks
Virological suppression at 12 and 48 weeks by modified ITT analysis will be stratified by ART-naïve versus first-line interruption status.
12 and 48 weeks
Secondary Outcome Differences Among ART-naïve Versus First-line Interruption Status by Per Protocol Analysis
Time Frame: 12, 24, and 48 weeks
Virological suppression at 12, 24, and 48 weeks by per protocol analysis will be stratified by ART-naïve versus first-line interruption status.
12, 24, and 48 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Gary Maartens, MMed, University of Cape Town

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 19, 2019

Primary Completion (Actual)

January 20, 2022

Study Completion (Actual)

June 28, 2022

Study Registration Dates

First Submitted

February 15, 2019

First Submitted That Met QC Criteria

February 21, 2019

First Posted (Actual)

February 22, 2019

Study Record Updates

Last Update Posted (Actual)

September 18, 2023

Last Update Submitted That Met QC Criteria

November 7, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be shared with other organizations 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.

IPD Sharing Time Frame

From the time the final results are published

IPD Sharing Access Criteria

Data will be shared with other organizations 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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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