- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03851588
Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis (RADIANT-TB)
Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis: a Phase 2 Non-comparative Randomised Controlled Trial
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
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Western Cape
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Cape Town, Western Cape, South Africa, 8001
- Khayelitsha Site B/Ubuntu Clinic
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
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
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.
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Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg.
Other Names:
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Placebo Comparator: Placebo dose
Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with placebo taken 12 hours later.
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Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is not given with a supplementary dose of dolutegravir 50 mg.
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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.
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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.
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12 weeks
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Virological Suppression at 24 Weeks (Per Protocol)
Time Frame: 24 weeks
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Proportion with HIV viral load <50 copies/mL at 24 weeks analyzed per protocol.
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24 weeks
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Virological Suppression at 48 Weeks (Modified ITT)
Time Frame: 48 weeks
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Proportion with HIV viral load <50 copies/mL at 48 weeks analyzed modified ITT.
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48 weeks
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Virological Suppression at 48 Weeks (Per Protocol)
Time Frame: 48 weeks
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Proportion with HIV viral load <50 copies/mL at 48 weeks analyzed per protocol.
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48 weeks
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CD4 Change at 24 and 48 Weeks
Time Frame: 24 and 48 weeks
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Change in CD4 count from screening at week 24 and week 48.
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24 and 48 weeks
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Dolutegravir Trough Concentrations
Time Frame: 4, 8, 12, 24, and 48 weeks
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Proportion with dolutegravir trough concentrations above the PA IC90 at weeks 4, 8, 12, 24, and 48.
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4, 8, 12, 24, and 48 weeks
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Grade 3 or 4 Adverse Events
Time Frame: 48 weeks
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Grade 3 or 4 drug-related adverse events will be accessed throughout the trial.
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48 weeks
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Change in Sleep Assessment From Baseline
Time Frame: 4, 8, 12, 16, 20, 24, and 48 weeks
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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).
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4, 8, 12, 16, 20, 24, and 48 weeks
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Change in Mental Health Assessment From Baseline
Time Frame: 12, 24, and 48 weeks
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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.
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12, 24, and 48 weeks
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Serious Adverse Events
Time Frame: 48 weeks
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Document any serious adverse events that occur throughout the trial.
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48 weeks
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Adverse Events Requiring Discontinuation of an ART Drug
Time Frame: 48 weeks
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Any adverse event that requires discontinuation of any drug in the ART regimen throughout the trial.
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48 weeks
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Antiretroviral Resistance Mutations Testing by Genotypic Resistance Assay in Participants With Virologic Failure
Time Frame: 24 and 48 weeks
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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.
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24 and 48 weeks
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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.
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24 weeks
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Secondary Outcome Differences Among ART-naïve Versus First-line Interruption Status by Modified ITT Analysis
Time Frame: 12 and 48 weeks
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Virological suppression at 12 and 48 weeks by modified ITT analysis will be stratified by ART-naïve versus first-line interruption status.
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12 and 48 weeks
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Secondary Outcome Differences Among ART-naïve Versus First-line Interruption Status by Per Protocol Analysis
Time Frame: 12, 24, and 48 weeks
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Virological suppression at 12, 24, and 48 weeks by per protocol analysis will be stratified by ART-naïve versus first-line interruption status.
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12, 24, and 48 weeks
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Gary Maartens, MMed, University of Cape Town
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Tuberculosis
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- HIV Integrase Inhibitors
- Integrase Inhibitors
- Dolutegravir
Other Study ID Numbers
- CIDRI003
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
- CSR
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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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