The purpose of this double-blind, randomised, controlled trial is to compare allergic outcomes in children following vaccination with acellular pertussis (aP) antigen (standard of care in Australia) ...given at 2 months of age versus whole cell pertussis (wP) in the infant vaccine schedule.
Up to 3000 Australian infants 6 to <12 weeks of age born ≥32 weeks gestation.
The intervention is a wP containing vaccine as the first scheduled pertussis vaccine dose instead of an aP containing vaccine.
The primary outcome is a binary indicator of history of IgE-mediated food allergy at the age of 12 months confirmed, where necessary, with an oral food challenge before 18 months of age. Secondary outcomes include (1) history of parent-reported clinician-diagnosed new onset of atopic dermatitis by 6 or 12 months of age with a positive skin prick test to any allergen before 12 months of age, (2) geometric mean concentration in pertussis toxin-specific IgG before and 21 to 35 days after a booster dose of aP at 18 months of age, and (3) sensitisation to at least one allergen by 12 months of age.
Operating characteristics of trial decision rules were evaluated by trial simulation. The selected rules for success and futility approximately maintain type I error of 0.05 and achieved power 0.85 for a reduction in the primary outcome from 10% in the control group to 7% in the intervention group.
A detailed, prospective statistical analysis plan (SAP) is presented for this Bayesian adaptive design. The plan was written by the trial statistician and details the study design, pre-specified adaptive elements, decision thresholds, statistical methods, and the simulations used to evaluate the operating characteristics of the trial. Application of this SAP will minimise bias and supports transparent and reproducible research.
Australia & New Zealand Clinical Trials Registry, ACTRN12617000065392 . Registered on 12 January 2017 STUDY PROTOCOL: https://doi.org/10.1136/bmjopen-2020-042838.
Background In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and ...epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. Methods and findings OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 88% of 74) versus aP (59 82% of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 97% of 73 versus 69 96% of 72 would agree to have the same schedule again). Conclusions Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. Trial registration Trial registered at the Australian and New Zealand Clinical 207 Trial Registry ( ACTRN12617000065392p ).
Abstract Background Untreated hepatitis C virus (HCV) infection can result in cirrhosis and hepatocellular cancer. Direct-acting antiviral (DAA) therapies are highly effective and have few side ...effects compared to older interferon-based therapy. Despite the Australian government providing subsidised and unrestricted access to DAA therapy for chronic HCV infection, uptake has not been sufficient to meet the global target of eliminating HCV as a public health threat by 2030. This study will offer people with HCV financial incentives of varying values in order to evaluate its effect on initiation of DAA therapy in primary care. Methods Australian adults (18 years or older) who self-report as having current untreated HCV infection can register to participate via an automated SMS-based system. Following self-screening for eligibility, registrants are offered a financial incentive of randomised value (AUD 0 to 1000) to initiate DAA therapy. Study treatment navigators contact registrants who have consented to be contacted, to complete eligibility assessment, outline the study procedures (including the requirement for participants to consult a primary care provider), obtain consent, and finalise enrolment. Enrolled participants receive their offered incentive on provision of evidence of DAA therapy initiation within 12 weeks of registration (primary endpoint). Balanced randomisation is used across the incentive range until the first analysis, after which response-adaptive randomisation will be used to update the assignment probabilities. For the primary analysis, a Bayesian 4-parameter EMAX model will be used to estimate the dose–response curve and contrast treatment initiation at each incentive value against the control arm (AUD 0). Specified secondary statistical and economic analyses will evaluate the effect of incentives on adherence to DAA therapy, virological response, and cost-effectiveness. Discussion This project seeks to gain an understanding of the dose–response relationship between incentive value and DAA treatment initiation, while maximising the number of people treated for HCV within fixed budget and time constraints. In doing so, we hope to offer policy-relevant recommendation(s) for the use of financial incentives as a pragmatic, efficient, and cost-effective approach to achieving elimination of HCV from Australia. Trial registration ANZCTR (anzctr.org.au), Identifier ACTRN12623000024640, Registered 11 January 2023 ( https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384923&isReview=true ).
While most Australian children are vaccinated, delays in vaccination can put them at risk from preventable infections. Widespread mobile phone ownership in Australia could allow automated short ...message service (SMS) reminders to be used as a low-cost strategy to effectively 'nudge' parents towards vaccinating their children on time.
AuTOMATIC is an adaptive randomised trial which aims to both evaluate and optimise the use of SMS reminders for improving the timely vaccination of children at primary care clinics across Australia. The trial will utilise high levels of digital automation to effect, including eligibility assessment, randomisation, delivery of intervention, data extraction and analysis, thereby allowing healthcare-embedded trial delivery. Up to 10,000 parents attending participating primary care clinics will be randomised to one of 12 different active SMS vaccine reminder content and timing arms or usual practice only (no SMS reminder). The primary outcome is vaccine receipt within 28 days of the scheduled date for the index vaccine (the first scheduled vaccine after randomisation). Secondary analyses will assess receipt and timeliness for all vaccine occasions in all children. Regular scheduled analyses will be performed using Bayesian inference and pre-specified trial decision rules, enabling response adaptive randomisation, suspension of any poorly performing arms and early stopping if a single best message is identified.
This study will aim to optimise SMS reminders for childhood vaccination in primary care clinics, directly comparing alternative message framing and message timing. We anticipate that the trial will be an exemplar in using Bayesian adaptive methodology to assess a readily implementable strategy in a wide population, capable of delivery due to the levels of digital automation. Methods and findings from this study will help to inform strategies for implementing reminders and embedding analytics in primary health care settings.
ANZCTR: ACTRN12618000789268 .
Adaptive clinical trials have designs that evolve over time because of changes to treatments or changes to the chance that participants will receive these treatments. These changes might introduce ...confounding that biases crude comparisons of the treatment arms and makes the results from standard reporting methods difficult to interpret for adaptive trials. To deal with this shortcoming, a reporting framework for adaptive trials was developed based on concurrently randomised cohort reporting. A concurrently randomised cohort is a subgroup of participants who all had the same treatments available and the same chance of receiving these treatments. The reporting of pre-randomisation characteristics and post-randomisation outcomes for each concurrently randomised cohort in the study is recommended. This approach provides a transparent and unbiased display of the degree of baseline balance and the randomised treatment comparisons for adaptive trials. The key concepts, terminology, and recommendations underlying concurrently randomised cohort reporting are presented, and its routine use in adaptive trial reporting is advocated.
The purpose of this double-blind, randomised, placebo-controlled, adaptive design trial with frequent interim analyses is to determine if Australian Indigenous children, who receive an additional ...(third) dose of human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to < 12 months, would improve protection against clinically significant all-cause gastroenteritis.
Up to 1000 Australian Aboriginal and Torres Strait Islander (hereafter Indigenous) infants aged 6 to < 12 months will be recruited from all regions of the Northern Territory.
The intervention is the addition of a third scheduled dose of human monovalent rotavirus vaccine.
ORVAC has two co-primary outcomes: (1) anti-rotavirus IgA seroconversion, defined as serum anti-rotavirus IgA ≥ 20 U/ml 28 to 55 days post Rotarix/placebo, and (2) time from randomisation to medical attendance for which the primary reason for presentation is acute gastroenteritis or acute diarrhoea illness before age 36 months. Secondary outcomes include (1) change in anti-rotavirus IgA log titre, (2) time from randomisation to hospitalisation with primary admission code presumed or confirmed acute diarrhoea illness before age 36 months, (3) time from randomisation to hospitalisation for which the admission is rotavirus confirmed diarrhoea illness before age 36 months and (4) time from randomisation to rotavirus infection (not necessarily requiring hospitalisation) meeting the jurisdictional definition before age 36 months.
A detailed, prospective statistical analysis plan is presented for this Bayesian adaptive design. The plan was written by the trial statistician and details the study design, pre-specified adaptative elements, decision thresholds, statistical methods and the simulations used to evaluate the operating characteristics of the trial. As at August 2020, four interim analyses have been run, but no stopping rules have been triggered. Application of this SAP will minimise bias and supports transparent and reproducible research.
Clinicaltrials.gov NCT02941107. Registered on 21 October 2016 ORIGINAL PROTOCOL FOR THE STUDY: https://doi.org/10.1136/bmjopen-2019-032549.
Providing culturally safe health care can contribute to improved health among Aboriginal people. However, little is known about how to make hospitals culturally safe for Aboriginal people. This study ...assessed the impact of an emergency department (ED)-based continuous quality improvement program on: the accuracy of recording of Aboriginal status in ED information systems; incomplete ED visits among Aboriginal patients; and the cultural appropriateness of ED systems and environments.
Between 2012 and 2014, the Aboriginal Identification in Hospitals Quality Improvement Program (AIHQIP) was implemented in eight EDs in NSW, Australia. A multiple baseline design and analysis of linked administrative data were used to assess program impact on the proportion of Aboriginal patients correctly identified as Aboriginal in ED information systems and incomplete ED visits in Aboriginal patients. Key informant interviews and document review were used to explore organisational changes.
In all EDs combined, the AIHQIP was not associated with a reduction in incomplete ED visits in Aboriginal people, nor did it influence the proportion of ED visits made by Aboriginal people that had an accurate recording of Aboriginal status. However, in two EDs it was associated with an increase in the trend of accurate recording of Aboriginality from baseline to the intervention period (odds ratio (OR) 1.31, p < 0.001 in ED 4 and OR 1.15, p = 0.020 in ED 5). In other words, the accuracy of recording of Aboriginality increased from 61.4 to 70% in ED 4 and from 72.6 to 73.9% in ED 5. If the program were not implemented, only a marginal increase would have occurred in ED 4 (from 61.4 to 64%) and, in ED 5, the accuracy of reporting would have decreased (from 72.6 to 71.1%). Organisational changes were achieved across EDs, including modifications to waiting areas and improved processes for identifying Aboriginal patients and managing incomplete visits.
The AIHQIP did not have an overall effect on the accuracy of recording of Aboriginal status or on levels of incomplete ED visits in Aboriginal patients. However, important organisational changes were achieved. Further research investigating the effectiveness of interventions to improve Aboriginal cultural safety is warranted.
SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic ...management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials.
ASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined.
This paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions.
Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).
Segmentation models aim to partition compositionally heterogeneous domains into homogeneous segments which may be reflective of biological function. Due to the latent nature of the segments a natural ...approach to segmentation that has gained favour recently uses Bayesian hidden Markov models (HMMs). Concomitantly in the last few decades, the free R programming language has become a dominant tool for computational statistics, visualization and data science. Therefore, this paper aims to fully exploit R to fit a Bayesian HMM for DNA segmentation. The joint posterior distribution of parameters in the model to be considered is derived followed by the algorithms that can be used for estimation. Functions following these algorithms (Gibbs Sampling, Data Augmentation and Label Switching) are then fully implemented in R. The methodology is assessed through extensive simulation studies and then being applied to analyse Simian Vacuolating virus (SV40). It is concluded that: (1) the algorithms and functions in R can correctly estimate sequence segmentation if the HMM structure is assumed; (2) the performance of the model improves with sequence length; (3) R is reasonably fast for short to medium sequence lengths and number of segments and (4) the segmentation of SV40 appears to correspond with the two major transcripts, early and late, that regulate the expression of SV40 genes.
Chronic wet cough, the most common symptom of a disease spectrum that encompasses protracted bacterial bronchitis (PBB) and bronchiectasis, is common among Aboriginal children. In the absence of any ...community prevalence data, and with the high burden of respiratory disease and the European Respiratory Society task force's recommendation to identify disease burden, we determined the prevalence of chronic wet cough and PBB in young Aboriginal children in four remote communities in north Western Australia.
A whole-population, prospective study was conducted. Aboriginal children aged ≤7 years were clinically assessed for chronic wet cough by paediatric respiratory clinicians between July 2018 and May 2019. Where children had a wet cough but parents reported a short or uncertain cough duration, children were followed up 1 month later. A medical record audit 6 weeks to 3 months later was used to determine those children with chronic wet cough who had PBB (based on response to antibiotics).
Of the 203 children, 191 (94%; median age 3.5 years, range 0-7 years) were enrolled. At the initial visit, chronic wet cough was present in 21 (11%), absent in 143 (75%) and unknown in 27 (14%). By follow-up, the total prevalence of chronic wet cough was 13% (95% CI 8-19%) and 10% (95% CI 7-17%) for PBB. Chronic wet cough was more common in the two communities with unsealed roads (19%) compared to the two with sealed roads (7%).
Given the relatively high prevalence, strategies to address reasons for and treatment of chronic wet cough and PBB in young Aboriginal children in remote north Western Australia are required.
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