Clinical trial NCT03851588: Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis
Official title: Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis: a Phase 2 Non-comparative Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Tuberculosis
Keywords: Antiretroviral therapy
Dolutegravir
Rifampicin
Tuberculosis
Drug-drug interaction
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: Wellcome Trust
name: Medecins Sans Frontieres, Netherlands
First posted: 2019-02-22
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Maximum age (years): 110
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel assignment of randomised groups with stratification by ART-naïve versus first-line interrupter status
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Virological Suppression at 24 Weeks
timeFrame: 24 weeks
Secondary outcomes:
measure: Virological Suppression at 12 Weeks (Modified ITT)
timeFrame: 12 weeks
measure: Virological Suppression at 24 Weeks (Per Protocol)
timeFrame: 24 weeks
measure: Virological Suppression at 48 Weeks (Modified ITT)
timeFrame: 48 weeks
measure: Virological Suppression at 48 Weeks (Per Protocol)
timeFrame: 48 weeks
measure: CD4 Change at 24 Weeks
timeFrame: 24 weeks
measure: Dolutegravir Trough Concentrations
timeFrame: 24 weeks
measure: Grade 3 or 4 Adverse Events
timeFrame: 48 weeks
measure: Change in Sleep Assessment From Baseline - Any Treatment Emergent Insomnia After Baseline Assessed at 4 Weekly Intervals Until Week 24 and Then Again at Week 48
timeFrame: Through 48 weeks
measure: Change in Mental Health Assessment From Baseline Through Week 48
timeFrame: Through 48 weeks
measure: Serious Adverse Events
timeFrame: 48 weeks
measure: Adverse Events Requiring Discontinuation of an ART Drug
timeFrame: 48 weeks
measure: Antiretroviral Resistance Mutations Testing by Genotypic Resistance Assay in Participants With Virologic Failure
timeFrame: Through 48 weeks
measure: Primary Outcome Differences Among ART-naïve Versus First-line Interruption Status
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: Khayelitsha Site B/Ubuntu Clinic
state: Western Cape
Study officials:
affiliation: University of Cape Town
name: Gary Maartens, MMed
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.