Journal Article > ProtocolFull Text
Trials. 2023 November 30; Volume 24 (Issue 1); 773.; DOI:10.1186/s13063-023-07701-6
Patil SB, Tamirat M, Khazhidinov K, Ardizzoni E, Atger M, et al.
Trials. 2023 November 30; Volume 24 (Issue 1); 773.; DOI:10.1186/s13063-023-07701-6
BACKGROUND
Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients.
METHODS
endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations.
DISCUSSION
This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen.
Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients.
METHODS
endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations.
DISCUSSION
This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen.
Journal Article > ReviewFull Text
Clin Microbiol Infect. 2023 July 21; Volume S1198-743X (Issue 23); 00339-7.; DOI:10.1016/j.cmi.2023.07.013
Motta I, Boeree M, Chesov D, Dheda K, Günther G, et al.
Clin Microbiol Infect. 2023 July 21; Volume S1198-743X (Issue 23); 00339-7.; DOI:10.1016/j.cmi.2023.07.013
BACKGROUND
Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances.
OBJECTIVES
This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials.
SOURCES
A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors' knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials).
CONTENT
This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research.
IMPLICATIONS
Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.
Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances.
OBJECTIVES
This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials.
SOURCES
A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors' knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials).
CONTENT
This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research.
IMPLICATIONS
Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.
Journal Article > ResearchFull Text
Lancet Respir Med. 2017 March 15 (Issue 4)
Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R, et al.
Lancet Respir Med. 2017 March 15 (Issue 4)
Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.
Journal Article > ProtocolFull Text
Trials. 2021 September 25; Volume 22 (Issue 1); 651.; DOI:10.1186/s13063-021-05491-3
Guglielmetti L, Ardizzoni E, Atger M, Baudin E, Berikova E, et al.
Trials. 2021 September 25; Volume 22 (Issue 1); 651.; DOI:10.1186/s13063-021-05491-3
BACKGROUND
Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings.
METHODS
endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations.
DISCUSSION
The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT02754765.
Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings.
METHODS
endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations.
DISCUSSION
The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT02754765.
Journal Article > ResearchFull Text
J Antimicrob Chemother. 2008 February 1; Volume 61 (Issue 2); DOI:10.1093/jac/dkm484
Cohen K, van Cutsem G, Boulle AM, McIlleron HM, Goemaere E, et al.
J Antimicrob Chemother. 2008 February 1; Volume 61 (Issue 2); DOI:10.1093/jac/dkm484
BACKGROUND AND OBJECTIVES: Nevirapine-containing antiretroviral therapy (ART) and rifampicin-based antitubercular therapy are commonly co-administered in Africa, where nevirapine is often the only available non-nucleoside reverse transcriptase inhibitor. Rifampicin induces the metabolism of nevirapine, but the extent of the reduction in nevirapine concentrations has varied widely in previous studies. We describe the steady-state pharmacokinetics of nevirapine during and after antitubercular therapy in South African patients. METHODS: Sixteen patients receiving ART including standard doses of nevirapine were admitted twice for intensive pharmacokinetic sampling: during and after rifampicin-based antitubercular therapy. RESULTS: Geometric mean ratios for nevirapine pharmacokinetic parameters during versus after antitubercular therapy were 0.61 [90% confidence interval (CI) 0.49-0.79] for Cmax, 0.64 (90% CI 0.52-0.80) for area under the curve up to 12 h (AUC(0-12)) and 0.68 (90% CI 0.53-0.86) for Cmin. Nevirapine Cmin was subtherapeutic (<3 mg/L) in six patients during antitubercular therapy (one of whom developed virological failure) and in none afterwards. There was no correlation between rifampicin concentrations and the degree of nevirapine induction assessed by the proportional change in nevirapine concentrations between the two admissions. The ratio of nevirapine AUC(0-12) to the AUC(0-12) of its 12-hydroxy metabolite was significantly lower in the presence of antitubercular therapy, consistent with induced metabolism. CONCLUSIONS: Nevirapine concentrations were significantly decreased by concomitant rifampicin-based antitubercular therapy and a high proportion of patients had subtherapeutic plasma concentrations. Further study in African patients is required to determine the implications for treatment outcomes.
Journal Article > ReviewFull Text
Lancet Infect Dis. 2015 June 1; Volume 15 (Issue 6); 711-720.; DOI:10.1016/S1473-3099(15)00007-9
Nachman S, Ahmed AO, Amanullah F, Becerra M, Botgros R, et al.
Lancet Infect Dis. 2015 June 1; Volume 15 (Issue 6); 711-720.; DOI:10.1016/S1473-3099(15)00007-9
Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.
Journal Article > CommentaryFull Text
Bull World Health Organ. 2014 January 1; Volume 92 (Issue 1); 68-74.; DOI:10.2471/BLT.13.122028
Brigden G, Nyang'wa BT, du Cros PAK, Varaine FFV, Hughes J, et al.
Bull World Health Organ. 2014 January 1; Volume 92 (Issue 1); 68-74.; DOI:10.2471/BLT.13.122028
Fewer than 20% of patients with multidrug-resistant (MDR) tuberculosis are receiving treatment and there is an urgent need to scale up treatment programmes. One of the biggest barriers to scale-up is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. For the first time in over 50 years, new drugs have been developed specifically to treat tuberculosis, with bedaquiline and potentially delamanid expected to be available soon for treatment of MDR cases. However, if the new drugs are merely added to the current treatment regimen, the new regimen will be at least as lengthy, cumbersome and toxic as the existing one. There is an urgent need for strategy and evidence on how to maximize the potential of the new drugs to improve outcomes and shorten treatment. We devised eight key principles for designing future treatment regimens to ensure that, once they are proven safe in clinical trials, they will be clinically effective and programmatically practicable. Regimens should contain at least one new class of drug; be broadly applicable for use against MDR and extensively drug-resistant Mycobacterium tuberculosis complex strains; contain three to five effective drugs, each from a different drug class; be delivered orally; have a simple dosing schedule; have a good side-effect profile that allows limited monitoring; last a maximum of 6 months; and have minimal interaction with antiretrovirals. Following these principles will maximize the potential of new compounds and help to overcome the clinical and programmatic disadvantages and scale-up constraints that plague the current regimen.