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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03851588
Recruitment Status : Recruiting
First Posted : February 22, 2019
Last Update Posted : January 18, 2020
Sponsor:
Collaborators:
Wellcome Trust
Medecins Sans Frontieres, Netherlands
Information provided by (Responsible Party):
Prof Gary Maartens, University of Cape Town

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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel assignment of randomised groups
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
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


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.




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.



Information from the National Library of Medicine

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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)
  • 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.

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): NCT03851588


Contacts
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Contact: Gary Maartens, MMed +27214066286 gary.maartens@uct.ac.za
Contact: Graeme Meintjes, PhD graemein@mweb.co.za

Locations
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South Africa
Khayelitsha Site B/Ubuntu Clinic Recruiting
Cape Town, Western Cape, South Africa, 8001
Contact: Rulan Griesel, MMed    +27216501992    grsrul001@myuct.ac.za   
Principal Investigator: Gary Maartens, MMed         
Sub-Investigator: Rulan Griesel, MMed         
Sponsors and Collaborators
University of Cape Town
Wellcome Trust
Medecins Sans Frontieres, Netherlands
Investigators
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Principal Investigator: Gary Maartens, MMed University of Cape Town

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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    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020
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.

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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 Prof Gary Maartens, University of Cape Town:
Antiretroviral therapy
Dolutegravir
Rifampicin
Tuberculosis
Drug-drug interaction
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Tenofovir
Lamivudine
Dolutegravir
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
HIV Integrase Inhibitors
Integrase Inhibitors