449 research outputs found
sj-docx-1-ctj-10.1177_17407745231176773 – Supplemental material for Handling intercurrent events and missing data in non-inferiority trials using the estimand framework: A tuberculosis case study
No full textSupplemental material, sj-docx-1-ctj-10.1177_17407745231176773 for Handling intercurrent events and missing data in non-inferiority trials using the estimand framework: A tuberculosis case study by Sunita Rehal, Suzie Cro, Patrick PJ Phillips, Katherine Fielding and James R Carpenter in Clinical Trials</p
Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape
No full textIn a Collection Review, Patrick Phillips and colleagues discuss developments in clinical trial design for the evaluation of TB therapeutics
Developing Tools for Late-Stage Regimen Development for Tuberculosis
No full textTuberculosis was the leading infectious disease killer, prior to the COVID-19 pandemic, and infected approximately 10 million people each year and kills approximately 1.5 million. Currently. drug-susceptible TB is treated with rifampin, isoniazid, pyrazinamide, and ethambutol for a minimum of six months, however even with full adherence to this long treatment, relapse and treatment failure each occur in approximately 5-10% of cases. Crucially, these treatments for drug-susceptible TB have not appreciably changed in over 50 years and current drug discovery and clinical development pipelines are in dire need of rapid innovation. In 2020, a landmark phase 3 trial successfully demonstrated noninferiority of a novel 4-month regimen compared to the current 6-month standard of care. TBTC Study 31/A5349 was a multicenter randomized controlled phase 3 non-inferiority trial that compared two four-month regimens (both replace rifampin with rifapentine, and one tests the additional substitution of ethambutol replaced by moxifloxacin) with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis. The regimen containing high dose rifapentine, moxifloxacin, isoniazid, and pyrazinamide successfully demonstrated noninferiority. Remarkably, Study 31/A5349 collected study wide pharmacokinetic samples of all six drugs offering us the first opportunity in the history of TB-research to link drug exposures to long term clinical outcomes.
Each of the six drugs were analyzed by non-linear mixed effects modeling and the typical population pharmacokinetic behavior, between subject variability of F, CL, and Vc, and their relationships with clinical characteristics and demographic covariates were thoroughly characterized. Model derived maximal plasma concentration and area under the curve (exposure) were then used in pharmacodynamic efficacy and toxicity analyses to determine optimal dosing. We conducted an integrated analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data from 2343 participants with drug-susceptible tuberculosis from Study 31/A5349. We compared two 4-month rifapentine-based regimens with and without moxifloxacin to a 6-month control regimen. We demonstrated the importance of achieving a high exposure to rifapentine in the 4-month rifapentine-moxifloxacin regimen to reduce the risk of TB-related unfavorable outcomes. We identified a low-risk subgroup where further treatment shortening and simplification is likely possible and a high-risk subgroup where longer treatment may be needed.
The integrated models built from this work were used in a variety of simulation work, (1) optimal dosing of the rifapentine-moxifloxacin regimen, (2) design of a novel risk-stratification duration-randomization phase II trial, (3) development of a clinical trial simulation tool to calculate statistical power and determine sample size, and (4) optimization of adaptive trial designs for phase II and III anti-tuberculosis agent.
Collectively, the dissertation research described here contributes to the optimal use of the first 4-month regimen for drug-susceptible tuberculosis and develops simulation tools for future development of novel therapeutics and interventions for the treatment and prevention of tuberculosis
Achievement of management targets associated with incident and long-term diagnosed diabetes among a representative population sample
No full textAim: To assess achievement of management targets among participants with diagnosed diabetes.
Methods: Participants in the North West Adelaide Health Study (n = 4060), a representative cohort aged 18+ years, were assessed at baseline in 2000-03 and follow-up in 2004-06. Diagnosed and undiagnosed diabetes were determined from fasting plasma glucose ( 7.0 mmol/L) and self-reported data.
Results: Baseline prevalences were 5.6% (95% CI 4.9-6.3) diagnosed and 1.0% (95% CI 0.7-1.4) undiagnosed diabetes. Annual incidences were 5.1 per 1000 diagnosed and 1.7 per 1000 undiagnosed diabetes. Among those with long-term diagnosed diabetes, 45.8% had HbA1c 7.0%, 26.8% had blood pressure < 130/85mmHg, 14.1% had body mass index 25, 88.5% were non- or ex-smokers, 19.2% had total cholesterol < 4 mmol/L, 61.9% had triglycerides < 2.0 mmol/L, 83.0% had HDL 1.0 mmol/L, and 45.6% had LDL < 2.5mmol/L. Participants with incident diagnosed diabetes were more likely to achieve HbA1c and less likely to achieve LDL targets than those with long-term diagnosed diabetes. Few people treated with hypoglycaemics, antihypertensives or statins were achieving targets.
Conclusions: Many people with diabetes are at risk of developing or worsening complications because they are not meeting recommended targets. Treatment with medication is also suboptimal, indicating a continued role for public health programs to reduce risk factors.Catherine R. Chittleborough, Katherine L. Baldock, Patrick J. Phillips, Anne W. Taylor the North West Adelaide Health Study Tea
Medicare-related service use and costs among people with diagnosed and undiagnosed diabetes and respiratory conditions
No full textObjective: To compare Medicare-related costs and service utilisation of people with diagnosed diabetes, asthma or chronic obstructive pulmonary disease (COPD) to those who were previously undiagnosed, and those without these conditions. Design, setting and participants: Representative cross-sectional study of people (18+ years) living in the north-west area of Adelaide. Participants were recruited by telephone interviews. Biomedical and self-report data for 2352 participants were linked to Medicare Australia Medicare Benefits Schedule (MBS) data from 1997 to 2002. Main outcome measures: Mean number and cost (benefit paid) of MBS services for people with diagnosed and previously undiagnosed diabetes, asthma, and COPD, and those without these conditions. Results: Mean (±SD) MBS costs were significantly greater for people diagnosed with diabetes (3307 ±2542), or COPD ($3779 ±2529) than for those without these conditions. MBS costs for people with asthma or COPD that had not yet been diagnosed were also significantly higher than for those without these conditions, although this was inconsistent across financial years. Conclusions: Diabetes, asthma, and COPD are costly conditions in terms of health service use. Costs associated with undiagnosed asthma and COPD are similar to their diagnosed states. Prevention of progression along each chronic disease continuum is likely to reduce costs.Catherine R. Chittleborough, Michael J. Burke, Anne W. Taylor, David H. Wilson, Patrick J. Phillips, Robert J. Adams, Richard E. Ruffin and the North West Adelaide Health Study Tea
Challenges of Phase III study design for trials of new drug regimens for the treatment of TB
No full text The standard WHO-recommended 6-month four-drug regimen for the treatment of tuberculosis is highly effective in clinical trial settings, but this level of efficacy is not always achieved in practice. Shorter, simpler regimens that promote better treatment adherence are urgently needed. In addition, it will be necessary to demonstrate noninferiority rather than superiority over the 6-month regimen. There are considerable challenges in designing and conducting noninferiority Phase III trials of new drug regimens. These include the choice of the margin of noninferiority, the primary outcome measure and strategies for handling nonassessable patients and reinfected patients in the analysis. Most of these trials are likely to be large and expensive and public–private partnerships will be required to conduct them. </jats:p
Gender-specific epidemiology of diabetes: A representative cross-sectional study
No full textBackground Diabetes and its associated complications are part of a chronic disease global epidemic that presents a public health challenge. Epidemiologists examining health differences between men and women are being challenged to recognise the biological and social constructions behind the terms 'sex' and/or 'gender', together with social epidemiology principles and the life course approach. This paper examines the epidemiology of a population with diabetes from the north-west metropolitan region of South Australia. Methods Data were used from a sub-population with diabetes (n = 263), from 4060 adults aged 18 years and over living in the north-west suburbs of Adelaide, South Australia. Eligible respondents were asked to participate in a telephone interview, a self-report questionnaire and a biomedical examination. Diabetes (undiagnosed and diagnosed) was determined using self-reported information and a fasting blood test administered to participants. Data were analysed using SPSS (Version 10.0) and EpiInfo (Version 6.0). Results Factors associated with diabetes for both men and women were being aged 40 years and over, and having a low gross annual household income, obesity and a family history of diabetes. In addition, being an ex-smoker and having low cholesterol levels were associated with diabetes among men. Among women, having a high waist-hip ratio, high blood pressure and reporting a previous cardiovascular event or mental health problem were associated with diabetes. Conclusion The results found that men and women with diabetes face different challenges in the management of their condition. Public health implications include a need for quality surveillance data, including epidemiological life course, social, behavioural, genetic and environmental factors. This will enrich the evidence base for health promotion professionals and allow policy makers to draw inferences and conclusions for interventions and planning purposesJanet F Grant, Neville Hicks, Anne W Taylor, Catherine R Chittleborough, Patrick J Phillips and The North West Adelaide Health Study Tea
Disruption of the developmental programme of Trypanosoma brucei by genetic ablation of TbZFP1, a differentiation-enriched CCCH protein
No full textThe regulation of differentiation is particularly important in microbial eukaryotes that inhabit multiple environments. The parasite Trypanosoma brucei is an extreme example of this, requiring exquisite gene regulation during transmission from mammals to the tsetse fly vector. Unusually, trypanosomes rely almost exclusively on post-transcriptional mechanisms for regulated gene expression. Hence, RNA binding proteins are potentially of great significance in controlling stage-regulated processes. We have previously identified TbZFP1 as a trypanosome molecule transiently enriched during differentiation to tsetse midgut procyclic forms. This small protein (101 amino acids) contains the unusual CCCH zinc finger, an RNA binding motif. Here, we show that genetic ablation of TbZFP1 compromises repositioning of the mitochondrial genome, a specific event in the strictly regulated differentiation programme. Despite this, other events that occur both before and after this remain intact. Significantly, this phenotype correlates with the TbZFP1 expression profile during differentiation. This is the first genetic disruption of a developmental regulator in T. brucei. It demonstrates that programmed events in parasite development can be uncoupled at the molecular level. It also further supports the importance of CCCH proteins in key aspects of trypanosome cell function
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