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| Name | Class |
|---|---|
| Wellcome Trust | OTHER |
| Medecins Sans Frontieres, Netherlands | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Supplementary dose | Active Comparator | Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later. |
|
| Placebo dose | Placebo Comparator | Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily with placebo taken 12 hours later. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Other | Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is not given with a supplementary dose of dolutegravir 50 mg. |
|
| 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 |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gary Maartens, MMed | University of Cape Town | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Khayelitsha Site B/Ubuntu Clinic | Cape Town | Western Cape | 8001 | South Africa |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37230101 | Derived | Griesel R, Zhao Y, Simmons B, Omar Z, Wiesner L, Keene CM, Hill AM, Meintjes G, Maartens G. Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial. Lancet HIV. 2023 Jul;10(7):e433-e441. doi: 10.1016/S2352-3018(23)00081-4. Epub 2023 May 22. | |
| 33954265 |
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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.
From the time the final results are published
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | mITT population at 24 weeks | Posted | Count of Participants | Participants | 24 weeks |
|
48 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Treatment resistant oesophageal candidiasis | Gastrointestinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Insomnia | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof Gary Maartens | University of Cape Town | 214066008 | +27 | gary.maartens@uct.ac.za |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 23, 2020 | Nov 7, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
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| ID | Term |
|---|---|
| C562325 | dolutegravir |
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Parallel assignment of randomised groups with stratification by ART-naïve versus first-line interrupter status
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| Dolutegravir 50 mg | Drug | Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg. |
|
|
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 Weeks | Change in CD4 count from screening at week 24. | 24 weeks |
| Dolutegravir Trough Concentrations | Proportion with dolutegravir trough concentrations above the PA IC90 at week 24 | 24 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 - 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 | 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. | Through 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. Any ART resistance mutations in participants with virological failure by week 48. | 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. | 24 weeks |
| 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. |
| 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| HIV-1 RNA log10 Viral Load | Median | Inter-Quartile Range | log10 copies/mL |
|
| CD4 | Median | Inter-Quartile Range | cells/mm3 |
|
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. |
|
|
| Secondary | Virological Suppression at 12 Weeks (Modified ITT) | Proportion with HIV viral load <50 copies/mL at 12 weeks analyzed modified ITT. | mITT population at 12 weeks | Posted | Count of Participants | Participants | 12 weeks |
|
|
|
| Secondary | Virological Suppression at 24 Weeks (Per Protocol) | Proportion with HIV viral load <50 copies/mL at 24 weeks analyzed per protocol. | Per protocol population at 24 weeks | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
| Secondary | Virological Suppression at 48 Weeks (Modified ITT) | Proportion with HIV viral load <50 copies/mL at 48 weeks analyzed modified ITT. | mITT population at 48 weeks | Posted | Count of Participants | Participants | 48 weeks |
|
|
|
| Secondary | Virological Suppression at 48 Weeks (Per Protocol) | Proportion with HIV viral load <50 copies/mL at 48 weeks analyzed per protocol. | Per protocol population at week 48 | Posted | Count of Participants | Participants | 48 weeks |
|
|
|
| Secondary | CD4 Change at 24 Weeks | Change in CD4 count from screening at week 24. | mITT population | Posted | Median | Inter-Quartile Range | cells/uL | 24 weeks |
|
|
|
| Secondary | Dolutegravir Trough Concentrations | Proportion with dolutegravir trough concentrations above the PA IC90 at week 24 | Participants with available dolutegravir trough concentrations at week 24 | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
| Secondary | Grade 3 or 4 Adverse Events | Grade 3 or 4 drug-related adverse events will be accessed throughout the trial. | Safety population | Posted | Count of Participants | Participants | 48 weeks |
|
|
|
| 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 | Safety population with available scores at baseline and with a baseline score <=7 | Posted | Count of Participants | Participants | Through 48 weeks |
|
|
|
| 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. | Safety population (all participants with baseline assessments available). | Posted | Count of Participants | Participants | Through 48 weeks |
|
|
|
| Secondary | Serious Adverse Events | Document any serious adverse events that occur throughout the trial. | Safety population | Posted | Count of Participants | Participants | 48 weeks |
|
|
|
| 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. | Posted | Count of Participants | Participants | 48 weeks |
|
|
|
| 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. | Safety population | Posted | Count of Participants | Participants | Through 48 weeks |
|
|
|
| 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. | mITT population | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
| 0 |
| 53 |
| 0 |
| 53 |
| 3 |
| 53 |
| EG001 | 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. | 3 | 55 | 5 | 55 | 0 | 55 |
| Lichenoid rash secondary to TB treatment | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Bowel obstruction | Gastrointestinal disorders | Systematic Assessment |
|
| Trauma | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Community acquired pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
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| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |