Population pharmacokinetics and pharmacodynamics of investigational regimens' drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): a prospective nested study protocol in a randomised controlled trial

Introduction Drug-resistant tuberculosis (TB) remains a global health threat, with little over 50% of patients successfully treated. Novel regimens like the ones being studied in the TB-PRACTECAL trial are urgently needed. Understanding anti-TB drug exposures could explain the success or failure of these trial regimens. We aim to study the relationship between the patients’ exposure to anti-TB drugs in TB-PRACTECAL investigational regimens and their treatment outcomes. Methods and analysis Adults with multidrug-resistant TB randomised to investigational regimens in TB-PRACTECAL will be recruited to a nested pharmacokinetic-pharmacodynamic (PKPD) study. Venous blood samples will be collected at 0, 2 and 23 hours postdose on day 1 and 0, 6.5 and 23 hours postdose during week 8 to quantify drug concentrations in plasma. Trough samples will be collected during week 12, 16, 20 and 24 visits. Opportunistic samples will be collected during weeks 32 and 72. Drug concentrations will be quantified using liquid chromatography-tandem mass spectrometry. Sputum samples will be collected at baseline, monthly to week 24 and then every 2 months to week 108 for MICs and bacillary load quantification. Full blood count, urea and electrolytes, liver function tests, lipase, ECGs and ophthalmology examinations will be conducted at least monthly during treatment. PK and PKPD models will be developed for each drug with nonlinear mixed effects methods. Optimal dosing will be investigated using Monte-Carlo simulations. Ethics and dissemination The study has been approved by the Médecins sans Frontières (MSF) Ethics Review Board, the LSHTM Ethics Committee, the Belarus RSPCPT ethics committee and PharmaEthics and the University of Witwatersrand Human Research ethics committee in South Africa. Written informed consent will be obtained from all participants. The study results will be shared with public health authorities, presented at scientific conferences and published in a peer-reviewed journal. Trial registration number NCT04081077; Pre-results

Caregiver perceptions and experiences of paediatric emergency department attendance during the COVID-19 pandemic: a mixed-methods study

BACKGROUND: During the early stages of the COVID-19 pandemic, concerns were raised about reduced attendance at hospitals, particularly in paediatric emergency departments, which could result in preventable poorer outcomes and late presentations among children requiring emergency care. We aimed to investigate the impact of COVID-19 on health-seeking behaviour and decision-making processes of caregivers presenting to paediatric emergency services at a National Health Service (NHS) Trust in London. MATERIALS AND METHODS: We conducted a mixed-methods study (survey and semi-structured interviews) across two hospital sites between November-December 2020. Data from each study were collected concurrently followed by data comparison. RESULTS: Overall, 100 caregivers participated in our study; 80 completed the survey only, two completed the interview only and 18 completed both. Our quantitative study found that almost two-thirds (63%, n = 62) of caregivers attended the department within two days of their child becoming ill. Our qualitative study identified three major themes which were underpinned by concepts of trust, safety and uncertainty and were assessed in relation to the temporal nature of the pandemic and the caregivers' journey to care. We found most caregivers balanced their concerns of COVID-19 and a perceived "overwhelmed" NHS by speaking to trusted sources, predominantly general practitioners (GPs). CONCLUSION: Caregivers have adapted their health-seeking behaviour throughout the pandemic as new information and guidance have been released. We identified several factors affecting decisions to attend; some existed before the pandemic (e.g., concerns for child's health) whilst others were due to the pandemic (e.g., perceived risks of transmission when accessing healthcare services). We recommend trusted medical professionals, particularly GPs, continue to provide reassurance to caregivers to seek emergency paediatric care when required. Communicating the hospital safety procedures and the importance of early intervention to caregivers could additionally provide reassurance to those concerned about the risks of accessing the hospital environment

Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice

Data Sharing in a Humanitarian Organization: The Experience of Médecins Sans Frontières

Open data and data sharing are essential for maximizing the benefits that can be obtained from institutional and research datasets [1]. In 2012, the medical humanitarian organization Me´decins Sans Frontieres (MSF) decided to adopt a data sharing policy for routinely collected clinical and research data (http://www.msf.org.uk/msf-data-sharing). Here we describe the policy’s principles, practicalities,and development process. We hope this paper will encourage and help other humanitarian and nongovernmental organizations to share their data with public health researchers for the benefit of the populations with which they work

Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan

Background: In 2016, World Health Organization guidelines conditionally recommended standardised shorter 9-12-month regimens for multidrug-resistant (MDR) tuberculosis (TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan. Methods: Consecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between September 1, 2013 and March 31, 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion. Results: Of 146 enrolled patients, 128 were included: 67 female (52.3%), median age 30.1 (interquartile range 23.8-44.4) years. At the end of treatment, 71.9% (92 out of 128) of patients achieved treatment success, with 68% (87 out of 128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failures with fluoroquinolone-resistance amplification in 8 patients (8 out of 22, 36.4%); 12 (9.4%) lost to follow-up; and 2 (1.5%) deaths. Recurrence occurred in one patient. Fourteen patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (adjusted OR 6.13, 95% CI 2.01; 18.63) and adherence <95% (adjusted OR 5.33, 95% CI 1.73; 16.36) were associated with unsuccessful outcome in multivariable logistic regression. Conclusions: Overall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of drug susceptibility testing-confirmed susceptibility

Randomised multicentre effectiveness trial of rapid syndromic testing by panel assay in children presenting to European emergency departments with acute respiratory infections-trial protocol for the ADEQUATE Paediatric trial

Introduction Syndromic panel assays, that is, using one test to simultaneously target multiple pathogens with overlapping signs and symptoms, have been integrated into routine paediatric care over the past decade, mainly for more severely ill and hospitalised patients. Their wider availability and short turnaround times open the possibility to apply them to non-hospitalised patients as well. In this context, it is important to trial how clinicians make use of pathogen detection data and if their early availability influences management decisions, particularly antibiotic use and hospitalisation. Methods and analysis Advanced Diagnostics for Enhanced QUality of Antibiotic prescription in respiratory Tract infections in Emergency rooms is an individually randomised, controlled, open-label effectiveness trial comparing the impact of a respiratory pathogen panel assay (BIOFIRE Respiratory Panel 2.1plus) used as a rapid syndromic test on nasopharyngeal swabs in addition to the standard of care versus standard of care alone. The trial will 1:1 randomise 520 participants under the age of 18 at 7 paediatric emergency departments in 5 European countries. Inclusion criteria for the trial consist of two sets, with the first describing respiratory tract infections in paediatric patients and the second describing the situation of potential management uncertainty in which test results may immediately affect management decisions. Enrolment started in July 2021 and is expected to be completed in early 2024. We will perform a two-sample t-test assuming a pooled variance estimate to compare the log-transformed mean time on antibiotic treatment (in hours) and number of days alive out of the hospital within 14 days after study enrolment between the control and intervention arms. Ethics and dissemination The trial protocol and materials were approved by research ethics committees in all participating countries. The respiratory pathogen panel assay is CE marked (assessed to meet European regulations) and FDA (United States Food and Drug Administration) cleared for diagnostic use. Participants and caregivers provide informed consent prior to study procedures commencing. The trial results will be published in peer-reviewed journals and at national and international conferences. Key messages will also be disseminated via press and social media where appropriate