A Phase 2 interventional study of Placebo and Dolutegravir 50 mg in HIV Infections and Tuberculosis, sponsored by University of Cape Town. Completed at 1 site in South Africa. Open to participants aged 18 Years to 110 Years. Per ClinicalTrials.gov, last updated 2024-07-18.
Sponsored by University of Cape Town · Phase 2, Interventional, and Treatment
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.
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.
1,417 studies on the registry are indexed under Tuberculosis; 208 are open to participants now.
This study's enrollment of 108 is below the median of 150 across 952 interventional studies indexed under Tuberculosis.
Browse Tuberculosis studies →University of Cape Town is the lead sponsor of 109 studies on the registry; 13 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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 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.
Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg.
Also known as: Tivicay 50 mg
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
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
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
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
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
CD4 Change at 24 Weeks
Change in CD4 count from screening at week 24.
Time frame: 24 weeks
Dolutegravir Trough Concentrations
Proportion with dolutegravir trough concentrations above the PA IC90 at week 24
Time frame: 24 weeks
Grade 3 or 4 Adverse Events
Grade 3 or 4 drug-related adverse events will be accessed throughout the trial.
Time frame: 48 weeks
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
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
Serious Adverse Events
Document any serious adverse events that occur throughout the trial.
Time frame: 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.
Time frame: 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. Any ART resistance mutations in participants with virological failure by week 48.
Time frame: Through 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.
Time frame: 24 weeks
| Milestone | Supplementary Dose | Placebo Dose |
|---|---|---|
| Started | 53 | 55 |
| Completed | 51 | 52 |
| Not completed | 2 | 3 |
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.
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Virological Suppression at 24 Weeks | 43 | 44 |
Proportion with HIV viral load \<50 copies/mL at 12 weeks analyzed modified ITT.
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Virological Suppression at 12 Weeks (Modified ITT) | 42 | 46 |
Proportion with HIV viral load \<50 copies/mL at 24 weeks analyzed per protocol.
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Virological Suppression at 24 Weeks (Per Protocol) | 43 | 44 |
Proportion with HIV viral load \<50 copies/mL at 48 weeks analyzed modified ITT.
| Participants | Supplemental Dolutegravir Arm | Placebo Arm |
|---|---|---|
| Virological Suppression at 48 Weeks (Modified ITT) | 34 | 35 |
Proportion with HIV viral load \<50 copies/mL at 48 weeks analyzed per protocol.
| Participants | Supplemental Dolutegravir Arm Per Protocol at Week 48 | Placebo Arm Per Protocol at Week 48 |
|---|---|---|
| Virological Suppression at 48 Weeks (Per Protocol) | 34 | 35 |
Change in CD4 count from screening at week 24.
| cells/uL | Supplementary Dose | Placebo Dose |
|---|---|---|
| CD4 Change at 24 Weeks | 111 (89 to 121) | 101 (84 to 114) |
Proportion with dolutegravir trough concentrations above the PA IC90 at week 24
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Dolutegravir Trough Concentrations | 32 | 34 |
Grade 3 or 4 drug-related adverse events will be accessed throughout the trial.
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Grade 3 or 4 Adverse Events | 11 | 10 |
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
| Participants | Supplementary Dose | 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 | 10 | 4 |
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.
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Change in Mental Health Assessment From Baseline Through Week 48 | 2 | 4 |
Document any serious adverse events that occur throughout the trial.
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Serious Adverse Events | 0 | 5 |
Any adverse event that requires discontinuation of any drug in the ART regimen throughout the trial.
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Adverse Events Requiring Discontinuation of an ART Drug | 0 | 0 |
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.
| Participants | Supplementary Dose | Placebo Dose |
|---|---|---|
| Antiretroviral Resistance Mutations Testing by Genotypic Resistance Assay in Participants With Virologic Failure | 3 | 3 |
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.
| Participants | ART Naive Supplemental Dolutegravir Arm | ART Naive Placebo Arm | First Line ART Interrupted Supplemental Dolutegravir Arm | First Line ART Interrupted Placebo Arm |
|---|---|---|---|---|
| Primary Outcome Differences Among ART-naïve Versus First-line Interruption Status | 36 | 36 | 7 | 8 |
Collected over 48 weeks. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Supplementary Dose | 0/53 (0%) | 0/53 (0%) | 3/53 (5.7%) |
| Placebo Dose | 3/55 (5.5%) | 5/55 (9.1%) | 0/55 (0%) |
| Event | Supplementary Dose | Placebo Dose |
|---|---|---|
| Treatment resistant oesophageal candidiasisGastrointestinal disorders | 0/53 | 1/55 |
| Lichenoid rash secondary to TB treatmentSkin and subcutaneous tissue disorders | 0/53 | 1/55 |
| Bowel obstructionGastrointestinal disorders | 0/53 | 1/55 |
| TraumaInjury, poisoning and procedural complications | 0/53 | 1/55 |
| Community acquired pneumoniaRespiratory, thoracic and mediastinal disorders | 0/53 | 1/55 |
| Event | Supplementary Dose | Placebo Dose |
|---|---|---|
| InsomniaNervous system disorders | 3/53 | 0/55 |
| Age, Continuous(years) | Supplementary Dose | Placebo Dose | Total |
|---|---|---|---|
| Median | 33 (28 to 38) | 37 (33 to 44) | 35 (31 to 40) |
| Sex: Female, Male(Participants) | Supplementary Dose | Placebo Dose | Total |
|---|---|---|---|
| Female | 19 | 19 | 38 |
| Male | 34 | 36 | 70 |
| Race (NIH/OMB)(Participants) | Supplementary Dose | Placebo Dose | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 53 | 55 | 108 |
| White | 0 | 0 | 0 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Supplementary Dose | Placebo Dose | Total |
|---|---|---|---|
| South Africa | 53 | 55 | 108 |
| HIV-1 RNA log10 Viral Load(log10 copies/mL) | Supplementary Dose | Placebo Dose | Total |
|---|---|---|---|
| Median | 5.1 (4.6 to 5.6) | 5.2 (4.6 to 5.7) | 5.2 (4.6 to 5.7) |
| CD4(cells/mm3) | Supplementary Dose | Placebo Dose | Total |
|---|---|---|---|
| Median | 197 (145 to 260) | 183 (145 to 316) | 188 (145 to 316) |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — 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 information: Study protocol, Sap, Icf, Csr
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