Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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HIV Infections, Tuberculosis

Intervention / Treatment
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* Other: Placebo
* Drug: Dolutegravir 50 mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel assignment of randomised groups with stratification by ART-naïve versus first-line interrupter status
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological Suppression at 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) | Proportion with HIV viral load <50 copies/mL at 12 weeks analyzed modified ITT. | 12 weeks | 
| Virological Suppression at 24 Weeks (Per Protocol) | Proportion with HIV viral load <50 copies/mL at 24 weeks analyzed per protocol. | 24 weeks | 
| Virological Suppression at 48 Weeks (Modified ITT) | Proportion with HIV viral load <50 copies/mL at 48 weeks analyzed modified ITT. | 48 weeks | 
| Virological Suppression at 48 Weeks (Per Protocol) | Proportion with HIV viral load <50 copies/mL at 48 weeks analyzed per protocol. | 48 weeks | 
| CD4 Change at 24 and 48 Weeks | Change in CD4 count from screening at week 24 and week 48. | 24 and 48 weeks | 
| Dolutegravir Trough Concentrations | 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 | Grade 3 or 4 drug-related adverse events will be accessed throughout the trial. | 48 weeks | 
| Change in Sleep Assessment From Baseline | 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). Please rate the current (i.e. last 2 weeks) severity of your insomnia problem(s): None, Mild, Moderate, Severe, Very Severe How satisfied/dissatisfied are you with your current sleep pattern? 0 - 5 (Very Satisfied - Very Dissatisfied) 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) 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) 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 | 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 | Document any serious adverse events that occur throughout the trial. | 48 weeks | 
| Adverse Events Requiring Discontinuation of an ART Drug | 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 | 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 | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug-drug interaction, Rifampicin, Antiretroviral therapy, Dolutegravir, Tuberculosis