HIV Infections, Tuberculosis
Conditions
Keywords
Antiretroviral therapy, Dolutegravir, Rifampicin, Tuberculosis, Drug-drug interaction
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.
Interventions
OTHERPlacebo
Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is not given with a supplementary dose of dolutegravir 50 mg.
Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg.
Sponsors
Wellcome Trust
Medecins Sans Frontieres, Netherlands
University of Cape Town
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Parallel assignment of randomised groups with stratification by ART-naïve versus first-line interrupter status
Eligibility
Sex/Gender
ALL
Age
18 Years to 110 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Virological Suppression at 24 Weeks | 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
| Measure | Time frame | Description |
|---|---|---|
| Virological Suppression at 24 Weeks (Per Protocol) | 24 weeks | Proportion with HIV viral load \<50 copies/mL at 24 weeks analyzed per protocol. |
| Virological Suppression at 48 Weeks (Modified ITT) | 48 weeks | Proportion with HIV viral load \<50 copies/mL at 48 weeks analyzed modified ITT. |
| Virological Suppression at 48 Weeks (Per Protocol) | 48 weeks | Proportion with HIV viral load \<50 copies/mL at 48 weeks analyzed per protocol. |
| CD4 Change at 24 Weeks | 24 weeks | Change in CD4 count from screening at week 24. |
| Dolutegravir Trough Concentrations | 24 weeks | Proportion with dolutegravir trough concentrations above the PA IC90 at week 24 |
| Grade 3 or 4 Adverse Events | 48 weeks | Grade 3 or 4 drug-related adverse events will be accessed throughout the trial. |
| Virological Suppression at 12 Weeks (Modified ITT) | 12 weeks | Proportion with HIV viral load \<50 copies/mL at 12 weeks analyzed modified ITT. |
| Change in Mental Health Assessment From Baseline Through Week 48 | Through 48 weeks | Modified MINI screen (MMS) Mental health questionnaire will be assessed by 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. MMS score increased is worsening MMS includes 22 questions answered yes/no; 2 questions related to experiencing a traumatic event were excluded for a 20 point scale. MMS was measured at baseline, week 12, and week 24 Presenting number of participants with increase in MMS of at least 1 point from baseline through 48 weeks. |
| Serious Adverse Events | 48 weeks | Document any serious adverse events that occur throughout the trial. |
| Adverse Events Requiring Discontinuation of an ART Drug | 48 weeks | Any adverse event that requires discontinuation of any drug in the ART regimen throughout the trial. |
| Antiretroviral Resistance Mutations Testing by Genotypic Resistance Assay in Participants With Virologic Failure | Through 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. Any ART resistance mutations in participants with virological failure by week 48. |
| Primary Outcome Differences Among ART-naïve Versus First-line Interruption Status | 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. |
| 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 | Through 48 weeks | Insomnia severity index (ISI scored from 0-28. Score categories: 0-7, no clinical significant insomnia; 8-14, sub-threshold insomnia; 15-21, clinical insomnia (moderate severity); 22-28, clinical insomnia (severe). Measures sleep patterns and how this influences daily functioning and quality of life (assessed through 48 weeks). Measure of participants with treatment emergent insomnia from baseline |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Supplementary Dose Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later.
Dolutegravir 50 mg: Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg. | 53 |
| Placebo Dose Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with placebo taken 12 hours later.
Placebo: Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is not given with a supplementary dose of dolutegravir 50 mg. | 55 |
| Total | 108 |
Baseline characteristics
| Characteristic | Supplementary Dose | Placebo Dose | Total |
|---|---|---|---|
| Age, Continuous | 33 years | 37 years | 35 years |
| CD4 | 197 cells/mm3 | 183 cells/mm3 | 188 cells/mm3 |
| HIV-1 RNA log10 Viral Load | 5.1 log10 copies/mL | 5.2 log10 copies/mL | 5.2 log10 copies/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 53 Participants | 55 Participants | 108 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa | 53 participants | 55 participants | 108 participants |
| Sex: Female, Male Female | 19 Participants | 19 Participants | 38 Participants |
| Sex: Female, Male Male | 34 Participants | 36 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 3 / 55 |
| other Total, other adverse events | 3 / 53 | 0 / 55 |
| serious Total, serious adverse events | 0 / 53 | 5 / 55 |
Outcome results
Primary
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.
Time frame: 24 weeks
Population: mITT population at 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Virological Suppression at 24 Weeks | 43 Participants |
| Placebo Dose | Virological Suppression at 24 Weeks | 44 Participants |
Secondary
Adverse Events Requiring Discontinuation of an ART Drug
Any adverse event that requires discontinuation of any drug in the ART regimen throughout the trial.
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Adverse Events Requiring Discontinuation of an ART Drug | 0 Participants |
| Placebo Dose | Adverse Events Requiring Discontinuation of an ART Drug | 0 Participants |
Secondary
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. Any ART resistance mutations in participants with virological failure by week 48.
Time frame: Through 48 weeks
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Antiretroviral Resistance Mutations Testing by Genotypic Resistance Assay in Participants With Virologic Failure | 3 Participants |
| Placebo Dose | Antiretroviral Resistance Mutations Testing by Genotypic Resistance Assay in Participants With Virologic Failure | 3 Participants |
Secondary
CD4 Change at 24 Weeks
Change in CD4 count from screening at week 24.
Time frame: 24 weeks
Population: mITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Supplementary Dose | CD4 Change at 24 Weeks | 111 cells/uL |
| Placebo Dose | CD4 Change at 24 Weeks | 101 cells/uL |
Secondary
Change in Mental Health Assessment From Baseline Through Week 48
Modified MINI screen (MMS) Mental health questionnaire will be assessed by 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. MMS score increased is worsening MMS includes 22 questions answered yes/no; 2 questions related to experiencing a traumatic event were excluded for a 20 point scale. MMS was measured at baseline, week 12, and week 24 Presenting number of participants with increase in MMS of at least 1 point from baseline through 48 weeks.
Time frame: Through 48 weeks
Population: Safety population (all participants with baseline assessments available).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Change in Mental Health Assessment From Baseline Through Week 48 | 2 Participants |
| Placebo Dose | Change in Mental Health Assessment From Baseline Through Week 48 | 4 Participants |
Secondary
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
Insomnia severity index (ISI scored from 0-28. Score categories: 0-7, no clinical significant insomnia; 8-14, sub-threshold insomnia; 15-21, clinical insomnia (moderate severity); 22-28, clinical insomnia (severe). Measures sleep patterns and how this influences daily functioning and quality of life (assessed through 48 weeks). Measure of participants with treatment emergent insomnia from baseline
Time frame: Through 48 weeks
Population: Safety population with available scores at baseline and with a baseline score \<=7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | 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 | 10 Participants |
| Placebo Dose | 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 | 4 Participants |
Secondary
Dolutegravir Trough Concentrations
Proportion with dolutegravir trough concentrations above the PA IC90 at week 24
Time frame: 24 weeks
Population: Participants with available dolutegravir trough concentrations at week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Dolutegravir Trough Concentrations | 32 Participants |
| Placebo Dose | Dolutegravir Trough Concentrations | 34 Participants |
Secondary
Grade 3 or 4 Adverse Events
Grade 3 or 4 drug-related adverse events will be accessed throughout the trial.
Time frame: 48 weeks
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Grade 3 or 4 Adverse Events | 11 Participants |
| Placebo Dose | Grade 3 or 4 Adverse Events | 10 Participants |
Secondary
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.
Time frame: 24 weeks
Population: mITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Primary Outcome Differences Among ART-naïve Versus First-line Interruption Status | 36 Participants |
| Placebo Dose | Primary Outcome Differences Among ART-naïve Versus First-line Interruption Status | 36 Participants |
| First Line ART Interrupted Supplemental Dolutegravir Arm | Primary Outcome Differences Among ART-naïve Versus First-line Interruption Status | 7 Participants |
| First Line ART Interrupted Placebo Arm | Primary Outcome Differences Among ART-naïve Versus First-line Interruption Status | 8 Participants |
Secondary
Serious Adverse Events
Document any serious adverse events that occur throughout the trial.
Time frame: 48 weeks
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Serious Adverse Events | 0 Participants |
| Placebo Dose | Serious Adverse Events | 5 Participants |
Secondary
Virological Suppression at 12 Weeks (Modified ITT)
Proportion with HIV viral load \<50 copies/mL at 12 weeks analyzed modified ITT.
Time frame: 12 weeks
Population: mITT population at 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Virological Suppression at 12 Weeks (Modified ITT) | 42 Participants |
| Placebo Dose | Virological Suppression at 12 Weeks (Modified ITT) | 46 Participants |
Secondary
Virological Suppression at 24 Weeks (Per Protocol)
Proportion with HIV viral load \<50 copies/mL at 24 weeks analyzed per protocol.
Time frame: 24 weeks
Population: Per protocol population at 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Virological Suppression at 24 Weeks (Per Protocol) | 43 Participants |
| Placebo Dose | Virological Suppression at 24 Weeks (Per Protocol) | 44 Participants |
Secondary
Virological Suppression at 48 Weeks (Modified ITT)
Proportion with HIV viral load \<50 copies/mL at 48 weeks analyzed modified ITT.
Time frame: 48 weeks
Population: mITT population at 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Virological Suppression at 48 Weeks (Modified ITT) | 34 Participants |
| Placebo Dose | Virological Suppression at 48 Weeks (Modified ITT) | 35 Participants |
Secondary
Virological Suppression at 48 Weeks (Per Protocol)
Proportion with HIV viral load \<50 copies/mL at 48 weeks analyzed per protocol.
Time frame: 48 weeks
Population: Per protocol population at week 48
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Supplementary Dose | Virological Suppression at 48 Weeks (Per Protocol) | 34 Participants |
| Placebo Dose | Virological Suppression at 48 Weeks (Per Protocol) | 35 Participants |