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

• ClinicalTrials.gov Identifier: NCT03851588
• Recruitment Status: Completed
• First Posted: February 22, 2019
• Last Update Posted: July 22, 2022
• Sponsor: University of Cape Town
• Collaborators: Wellcome Trust; Medecins Sans Frontieres, Netherlands
• Information provided by (Responsible Party): Prof Gary Maartens, University of Cape Town

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV Infections; Tuberculosis	Other: Placebo; Drug: Dolutegravir 50 mg	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 108 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Parallel assignment of randomised groups with stratification by ART-naïve versus first-line interrupter status
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis: a Phase 2 Non-comparative Randomised Controlled Trial
• Actual Study Start Date: December 19, 2019
• Actual Primary Completion Date: January 20, 2022
• Actual Study Completion Date: June 28, 2022

Arms and Interventions

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.	Drug: Dolutegravir 50 mg; Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg.; Other Name: Tivicay 50 mg
Placebo Comparator: Placebo dose; Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with placebo taken 12 hours later.	Other: Placebo; Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is not given with a supplementary dose of dolutegravir 50 mg.

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. Virological suppression at 12 and 24 weeks (per protocol) [ Time Frame: 12 and 24 weeks ]
   Proportion with HIV viral load <50 copies/mL at 12 and 24 weeks analyzed per protocol.
3. 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.
4. 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.
5. 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.
6. 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.
7. Grade 3 or 4 adverse events [ Time Frame: 48 weeks ]
   Grade 3 or 4 drug-related adverse events will be accessed throughout the trial.
8. 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)
9. 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.
10. Serious adverse events [ Time Frame: 48 weeks ]
    Document any serious adverse events that occur throughout the trial.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 110 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

South Africa

Khayelitsha Site B/Ubuntu Clinic

Cape Town, Western Cape, South Africa, 8001

Sponsors and Collaborators

University of Cape Town

Wellcome Trust

Medecins Sans Frontieres, Netherlands

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Griesel R, Hill A, Meintjes G, Maartens G. Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial. Wellcome Open Res. 2021 Jan 11;6:1. doi: 10.12688/wellcomeopenres.16473.1. eCollection 2021.

• Responsible Party: Prof Gary Maartens, Head of Division of Clinical Pharmacology, University of Cape Town
• ClinicalTrials.gov Identifier: NCT03851588
• Other Study ID Numbers: CIDRI003
• First Posted: February 22, 2019
• Last Update Posted: July 22, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• 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 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.

• 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 Prof Gary Maartens, University of Cape Town:

Antiretroviral therapy; Dolutegravir; Rifampicin; Tuberculosis; Drug-drug interaction

Additional relevant MeSH terms:

Tuberculosis; Infections; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Dolutegravir; HIV Integrase Inhibitors; Integrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents