{"id":6329,"date":"2023-10-05T10:23:44","date_gmt":"2023-10-05T09:23:44","guid":{"rendered":"https:\/\/medicine.st-andrews.ac.uk\/tbtrials\/?page_id=6329"},"modified":"2026-03-11T15:36:20","modified_gmt":"2026-03-11T15:36:20","slug":"publications","status":"publish","type":"page","link":"https:\/\/medicine.st-andrews.ac.uk\/tbtrials\/publications\/","title":{"rendered":"Publications"},"content":{"rendered":"

[et_pb_section fb_built=”1″ admin_label=”Section” _builder_version=”4.22.2″ custom_margin=”180px||||false|false” global_colors_info=”{}”][et_pb_row _builder_version=”4.16″ global_colors_info=”{}” max_width=”none”][et_pb_column type=”4_4″ _builder_version=”4.16″ custom_padding=”|||” global_colors_info=”{}” custom_padding__hover=”|||”][et_pb_heading title=”Recent Publications” admin_label=”Recent Publications” _builder_version=”4.22.2″ _module_preset=”default” global_colors_info=”{}” custom_margin=”||15px|||”][\/et_pb_heading][et_pb_text _builder_version=”4.27.5″ _module_preset=”default” hover_enabled=”0″ global_colors_info=”{}” sticky_enabled=”0″]We are delighted that our paper was accepted in the Lancet and this has been achieved through the efforts of the whole consortium a mammoth achievement, depending as it does, on the efforts of every member who has participated in delivering the trial.\u00a0 The excerpt below has been taken from the publication and the full text can be accessed here: https:\/\/www.thelancet.com\/action\/showPdf?pii=S1473-3099%2824%2900223-8<\/a><\/p>\n

Articles <\/strong>Volume 24,\u00a0Issue 9<\/a>p1003-1014September 2024 Open access<\/em><\/strong><\/p>\n

Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial<\/strong><\/p>\n

Muge\u00a0Cevik,\u00a0MD<\/a>a<\/sup>\u00a0mc349@st-andrews.ac.uk<\/a>\u00a0\u2219\u00a0Lindsay C\u00a0Thompson,\u00a0MPhil<\/a>b<\/sup>\u00a0\u2219\u00a0Caryn\u00a0Upton,\u00a0MD<\/a>d<\/sup>\u00a0\u2219\u00a0Val\u00e9ria Cavalcanti\u00a0Rolla<\/a>e<\/sup>\u00a0\u2219\u00a0Mookho\u00a0Malahleha,\u00a0MD<\/a>f<\/sup>\u00a0\u2219\u00a0Blandina\u00a0Mmbaga,\u00a0PhD<\/a>g<\/sup>\u00a0\u2219\u00a0Nosipho\u00a0Ngubane,\u00a0MD<\/a>h<\/sup><\/span>\u00a0\u2219\u00a0Zamzurina\u00a0Abu Bakar,\u00a0MD<\/a>i<\/sup><\/span>\u00a0\u2219\u00a0Mohammed\u00a0Rassool,\u00a0MD<\/a>j<\/sup><\/span>\u00a0\u2219\u00a0Ebrahim\u00a0Variava,\u00a0MD<\/a>k<\/sup><\/span>\u00a0\u2219\u00a0Rodney\u00a0Dawson,\u00a0MD<\/a>l<\/sup><\/span>\u00a0\u2219\u00a0Suzanne\u00a0Staples,\u00a0DPhil<\/a>m<\/sup><\/span>\u00a0\u2219\u00a0Umesh\u00a0Lalloo,\u00a0MD<\/a>n<\/sup><\/span>\u00a0\u2219\u00a0Cheryl\u00a0Louw,\u00a0MD<\/a>o<\/sup><\/span>\u00a0\u2219\u00a0Francesca\u00a0Conradie,\u00a0MD<\/a>p<\/sup><\/span>\u00a0\u2219\u00a0Marika\u00a0Eristavi,\u00a0MD<\/a>q<\/sup><\/span>\u00a0\u2219\u00a0Anastasia\u00a0Samoilova,\u00a0MD<\/a>r<\/sup><\/span>\u00a0\u2219\u00a0Sergey N\u00a0Skornyakov,\u00a0MD<\/a>s<\/sup><\/span>\u00a0\u2219\u00a0Niyanda Elias\u00a0Ntinginya,\u00a0PhD<\/a>t<\/sup><\/span>\u00a0\u2219\u00a0Frederick\u00a0Haraka,\u00a0MD<\/a>u<\/sup><\/span>\u00a0\u2219\u00a0George\u00a0Praygod,\u00a0PhD<\/a>v<\/sup><\/span>\u00a0\u2219\u00a0Harriett\u00a0Mayanja-Kizza,\u00a0PhD<\/a>w<\/sup><\/span>\u00a0\u2219\u00a0Janice\u00a0Caoili,\u00a0MD<\/a>x<\/sup><\/span>\u00a0\u2219\u00a0Vincent\u00a0Balanag,\u00a0MD<\/a>y<\/sup><\/span>\u00a0\u2219\u00a0Prof\u00a0Margareth Pretti\u00a0Dalcolmo,\u00a0PhD<\/a>z<\/sup><\/span>\u00a0\u2219\u00a0Prof\u00a0Timothy\u00a0McHugh,\u00a0PhD<\/a>c<\/sup><\/span>\u00a0\u2219\u00a0Robert\u00a0Hunt,\u00a0BSc<\/a>c<\/sup><\/span>\u00a0\u2219\u00a0Priya\u00a0Solanki,\u00a0MSc<\/a>c<\/sup><\/span>\u00a0\u2219\u00a0Anna\u00a0Bateson,\u00a0PhD<\/a>c<\/sup><\/span>\u00a0\u2219\u00a0Angela M\u00a0Crook,\u00a0PhD<\/a>b<\/sup><\/span>\u00a0\u2219\u00a0Stella\u00a0Fabiane,\u00a0PhD<\/a>b<\/sup><\/span>\u00a0\u2219\u00a0Juliano\u00a0Timm,\u00a0PhD<\/a>aa<\/sup><\/span>\u00a0\u2219\u00a0Eugene\u00a0Sun,\u00a0MD<\/a>aa<\/sup><\/span>\u00a0\u2219\u00a0Melvin\u00a0Spigelman,\u00a0MD<\/a>aa<\/sup><\/span>\u00a0\u2219\u00a0Derek J\u00a0Sloan,\u00a0PhD<\/a>a<\/sup><\/span>\u00a0\u2219\u00a0Prof\u00a0Stephen H\u00a0Gillespie,\u00a0DSc<\/a>a<\/sup><\/span>\u00a0on behalf of\u00a0SimpliciTB Consortium<\/a><\/span><\/p>\n

Summary<\/strong><\/p>\n

Background<\/p>\n

The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB.<\/p>\n

Methods<\/p>\n

SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had\u00a0Mycobacterium tuberculosis<\/em>\u00a0with sensitivity to rifampicin and isoniazid. Participants with DR-TB had\u00a0M tuberculosis<\/em>\u00a0with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with\u00a0ClinicalTrials.gov<\/a>\u00a0(NCT03338621<\/a>) and is completed.<\/p>\n

Findings<\/p>\n

Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2\u00b793 (95% CI 2\u00b717\u20133\u00b796; p<0\u00b70001). Median time to negative culture (TTN) was 6 weeks (IQR 4\u20138) on 4 months of BPaMZ and 11 weeks (6\u201312) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3\u20137). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]).<\/p>\n

Interpretation<\/p>\n

For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments.<\/p>\n

Funding<\/p>\n

TB Alliance.
\n[\/et_pb_text][et_pb_divider _builder_version=”4.27.5″ _module_preset=”default” hover_enabled=”0″ sticky_enabled=”0″][\/et_pb_divider][et_pb_text admin_label=”Recent Publications (list with links)” _builder_version=”4.27.5″ background_size=”initial” background_position=”top_left” background_repeat=”repeat” hover_enabled=”0″ global_colors_info=”{}” sticky_enabled=”0″]<\/p>\n

Recent publications can be found by clicking on the text below:<\/h2>\n