The AuTOMATIC trial: a study protocol for a multi-arm Bayesian adaptive randomised controlled trial of text messaging to improve childhood immunisation coverage.

BACKGROUND: 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. METHODS: 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. DISCUSSION: 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. TRIAL REGISTRATION: ANZCTR: ACTRN12618000789268 .

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.

BACKGROUND: 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. METHODS: 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. DISCUSSION: 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. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.

BACKGROUND: 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. METHODS: 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. DISCUSSION: 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. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

Statistical analysis plan for the OPTIMUM study: optimising immunisation using mixed schedules, an adaptive randomised controlled trial of a mixed whole-cell/acellular pertussis vaccine schedule.

OBJECTIVE: 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. PARTICIPANTS: Up to 3000 Australian infants 6 to <12 weeks of age born ≥32 weeks gestation. INTERVENTIONS: The intervention is a wP containing vaccine as the first scheduled pertussis vaccine dose instead of an aP containing vaccine. OUTCOMES: 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. RESULTS: 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. DISCUSSION: 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. TRIAL REGISTRATION: Australia & New Zealand Clinical Trials Registry, ACTRN12617000065392 . Registered on 12 January 2017 STUDY PROTOCOL: https://doi.org/10.1136/bmjopen-2020-042838.

Recognition and Management of Protracted Bacterial Bronchitis in Australian Aboriginal Children: A Knowledge Translation Approach.

BACKGROUND: Chronic wet cough in children is the hallmark symptom of protracted bacterial bronchitis (PBB) and if left untreated can lead to bronchiectasis, which is prevalent in Indigenous populations. Underrecognition of chronic wet cough by parents and clinicians and underdiagnosis of PBB by clinicians are known. RESEARCH QUESTION: We aimed to improve recognition and management of chronic wet cough in Aboriginal children using knowledge translation (KT), a methodologic approach that can be adapted for use in Indigenous contexts to facilitate effective and sustained translation of research into practice. STUDY DESIGN AND METHODS: A mixed-methods KT study undertaken at a remote-based Aboriginal primary medical service (February 2017 to December 2019). Our KT strategy included the following: (1) culturally secure (ie, ensuring Aboriginal people are treated regarding their unique cultural needs and differences) knowledge dissemination to facilitate family health seeking for chronic wet cough in children, and (2) an implementation strategy to facilitate correct diagnosis and management of chronic wet cough and PBB by physicians. RESULTS: Post-KT, health seeking for chronic wet cough increased by 184% (pre = eight of 630 children [1.3%], post = 23 of 636 children [3.6%]; P = .007; 95% CI, 0.7%-4.0%). Physician proficiency in management of chronic wet cough improved significantly as reflected by improved chronic cough-related quality of life (P < .001; 95% CI, 0.8-3.0) and improved physician assessment of cough quality (P < .001; 95% CI, 10.4%-23.0%), duration (P < .001; 95% CI, 11.1%-24.1%), and appropriate antibiotic prescription (P = .010; 95% CI, 6.6%-55.7%). INTERPRETATION: Health seeking for children with chronic wet cough can be facilitated through provision of culturally secure health information. Physician proficiency in the management of PBB can be improved with KT strategies which include training in culturally informed management, leading to better health outcomes. Comprehensive strategies that include both families and health systems are required to ensure that chronic wet cough in children is detected and optimally managed.

OPTIMUM study protocol: an adaptive randomised controlled trial of a mixed whole-cell/acellular pertussis vaccine schedule.

INTRODUCTION: Combination vaccines containing whole-cell pertussis antigens were phased out from the Australian national immunisation programme between 1997 and 1999 and replaced by the less reactogenic acellular pertussis (aP) antigens. In a large case-control study of Australian children born during the transition period, those with allergist diagnosed IgE-mediated food allergy were less likely to have received whole-cell vaccine in early infancy than matched population controls (OR: 0.77 (95% CI, 0.62 to 0.95)). We hypothesise that a single dose of whole-cell vaccine in early infancy is protective against IgE-mediated food allergy. METHODS AND ANALYSIS: This adaptive double-blind randomised controlled trial is investigating whether a mixed whole-cell/aP vaccine schedule prevents allergic disease in the first year of life. The primary outcome is IgE-mediated food allergy by 12 months of age. Secondary outcomes include new onset of atopic dermatitis by 6 or 12 months of age; sensitisation to at least one allergen by 12 months of age; seroconversion in anti-pertussis toxin IgG titres after vaccination with aP booster at 18 months of age; and solicited systemic and local adverse events following immunisation with pertussis-containing vaccines. Analyses will be performed using a Bayesian group sequential design. ETHICS AND DISSEMINATION: This study has been approved by the Child and Adolescent Health Service Human Research Ethics Committee, Perth, Western Australia (RGS 00019). The investigators will ensure that this trial is conducted in accordance with the principles of the Declaration of Helsinki and with the International Conference on Harmonisation Guidelines for Good Clinical Practice. Individual consent will be requested. Parents will be reimbursed reasonable travel and parking costs to attend the study visits. The dissemination of these research findings will follow the National Health and Medical Research Council of Australia Open Access Policy. TRIAL REGISTRATION NUMBER: ACTRN12617000065392p.

The ORVAC trial: a phase IV, double-blind, randomised, placebo-controlled clinical trial of a third scheduled dose of Rotarix rotavirus vaccine in Australian Indigenous infants to improve protection against gastroenteritis: a statistical analysis plan.

OBJECTIVE: 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. PARTICIPANTS: 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. INTERVENTIONS: The intervention is the addition of a third scheduled dose of human monovalent rotavirus vaccine. CO-PRIMARY AND SECONDARY OUTCOME MEASURES: 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. DISCUSSION: 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. TRIAL REGISTRATION: Clinicaltrials.gov NCT02941107. Registered on 21 October 2016 ORIGINAL PROTOCOL FOR THE STUDY: https://doi.org/10.1136/bmjopen-2019-032549.

Adverse events following HPV vaccination: 11 years of surveillance in Australia.

BACKGROUND: Australia was the first country to implement a fully funded vaccination program with quadrivalent human papillomavirus vaccine (4vHPV) in 2007, including males from 2013. We examined adverse events (AE) following vaccination with 4vHPV from 11 years of post-marketing data, focusing on a period of enhanced surveillance and adverse events of special interest (AESI). METHODS: AE following 4vHPV doses administered between April 2007 and December 2017 reported to Australia's national regulator, the Therapeutic Goods Administration, were examined; reports collected during enhanced surveillance in 2013 and 2014 were analyzed separately. Age and sex-specific rates, using denominator data from the national HPV vaccination register, were determined. Pre-specified AESI were identified using Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Terms and examined in detail. FINDINGS: Following nine million doses of 4vHPV vaccine administered in Australia, 4551 AE reports were identified. The crude reporting rate was 39.8 per 100 000 doses in the funded cohorts, excluding the enhanced surveillance period. The reported rate of syncope in 12 to 13-year-old males and females was 29.6 per 100 000 doses during enhanced surveillance and 7.1 per 100 000 doses during the remaining study period; rates of syncope were higher in younger compared to older adolescents. The rate of anaphylaxis (0.32 per 100 000 doses) was consistent with published rates. Other AESI including autoimmune disease, postural orthostatic tachycardia syndrome, primary ovarian insufficiency, Guillain-Barré syndrome, complex regional pain syndrome and venous thromboembolism, were reported at low rates and analysis did not reveal unexpected patterns that would suggest causal association. INTERPRETATION: AESI, apart from syncope, were reported rarely. The higher rate of syncope among younger adolescents highlights the need for management protocols to prevent syncope-related injury. Analysis of this large, longitudinal dataset in a country with high vaccine uptake, including a period of enhanced surveillance, affirms the safety profile of 4vHPV.

FeBRILe3 Project: protocol for a prospective pragmatic, multisite observational study and safety evaluation assessing Fever, Blood cultures and Readiness for discharge in Infants Less than 3 months old.

INTRODUCTION: The purpose of this observational study is to assess the safety and impact of the introduction of a clinical practice guideline (CPG) recommending early discharge of infants with fever without source who are at low risk of serious bacterial infection (SBI). We hypothesise that implementation of this guideline will be associated with a rate of unplanned readmission to hospital (within 7 days of discharge) which is similar (ie, non-inferior) to that observed under previous standard practice. METHODS AND ANALYSIS: This observational study is a prospective pragmatic, multisite safety assessment and impact project. It will evaluate the safety of a CPG which allows febrile infants fulfilling low-risk criteria to be discharged early from hospital if their blood cultures demonstrate no growth at 24 hours (compared with previous minimum 48 hours admission). This guideline has been implemented at two Western Australian metropolitan hospitals. Infants aged <3 months (chronological or corrected for premature birth before 37 weeks gestation) presenting with fever without source will be included. The primary outcome is readmission to hospital due to clinical deterioration/caregiver concern within 7 days of discharge, identified through review of electronic admission details and study-specific caregiver surveys. Secondary outcomes include rates of SBI, hospital lengths of stay compared with previous practice, clinician guideline adherence and caregiver satisfaction with the discharge process. Analysis will be within a sequential Bayesian safety monitoring framework, which incorporates new information and updates the evidence for guideline safety relative to previous practice (historical control) at prespecified interim analyses. Demographic and clinical information will be summarised. ETHICS AND DISSEMINATION: Ethics approval and waiver of consent for data collection has been granted by the Child and Adolescent Health Service Human Research Ethics Committee (RGS0000001415). Caregivers will have the option to opt out of survey follow-up. Results will be disseminated via peer-reviewed publication. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619001010189).

Safety of live attenuated herpes zoster vaccine in adults 70-79 years: A self-controlled case series analysis using primary care data from Australia's MedicineInsight program.

BACKGROUND: Australia introduced a funded shingles vaccination program for older adults in November 2016, administered predominantly in primary care clinics. MedicineInsight, a nationally representative primary care database, was used to investigate the risk of pre-specified outcomes following live attenuated herpes zoster vaccine (ZVL) in Australia. METHODS: Individuals aged 70-79 years who received ZVL between 1 November 2016 and 31 July 2018 were identified from MedicineInsight. The self-controlled case series (SCCS) method was used to estimate the seasonally-adjusted relative incidence (RI) of seven pre-specified outcome events (injection site reaction (ISR) [positive control], burn [negative control], myocardial infarction (MI), stroke, rash, rash with an antiviral prescription, and clinical attendance) during a plausible post-vaccination at-risk window compared with times distant from vaccination. Sensitivity analyses examined the effect of common concomitant vaccinations and restriction to first outcome events. RESULTS: A total of 332,988 vaccination encounters among 150,054 individuals were identified during the study period; over 2 million clinical attendances were observed. There was an increased RI of ISR in the seven days following ZVL (RI = 77.4, 95% CI 48.1-124.6); the RI of clinical attendance (RI = 0.94, 95% CI 0.94-0.95) and stroke (RI = 0.58, 95% CI 0.44-0.78) were lower in the 42 days following administration of ZVL compared to control periods. There was no evidence of a change in the RI of MI (RI = 0.74, 95% CI 0.41-1.33), rash (RI = 0.97, 95% CI 0.88-1.08), or rash with antiviral prescription (RI = 0.83, 95% CI 0.62-1.10) in the 42 days following ZVL compared to control periods. CONCLUSION: No new safety concerns were identified for ZVL in this study based on a novel, Australian primary care data source. An expected increased risk of ISR was identified; findings in relation to cardiovascular disease were reassuring but require confirmation using additional data, including hospital records.

Prevalence of chronic wet cough and protracted bacterial bronchitis in Aboriginal children.

BACKGROUND: 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. METHODS: 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). RESULTS: 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%). CONCLUSION: 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.

Can a continuous quality improvement program create culturally safe emergency departments for Aboriginal people in Australia? A multiple baseline study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Contribution of maternal age, medical and obstetric history to maternal and perinatal morbidity/mortality for women aged 35 or older.

BACKGROUND: As age is not modifiable, pregnancy risk information based on age alone is unhelpful for older women. AIM: To determine severe morbidity/mortality rates for women aged ≥35 years according to maternal profile based on parity, pre-existing medical conditions and prior pregnancy complications, and to assess the independent contribution of age. MATERIALS AND METHODS: Population-based record-linkage study using NSW hospitalisation and birth records 2006-2012. Maternal and perinatal mortality/morbidity were assessed for non-anomalous singleton births to women aged ≥35 years. RESULTS: For 117 357 pregnancies among 99 375 women aged ≥35 years, the median age at delivery was 37 years (range 35-56 years), including: 35 652 (30.4%) multiparae without pre-existing medical or obstetric complications, 33,058 (28.2%) nulliparae without pre-existing medical conditions and 30 325 (25.8%) multiparae with prior pregnancy complications. Maternal and perinatal mortality/morbidity varied by maternal profile with ranges of 0.9-3.5% and 2.4-11.9%, respectively. For nulliparae, each five-year increase in age did not contribute significantly to maternal risk after controlling for medical conditions (adjustedodds ratio 1.08, 95% CI 0.93-1.25), but did confer perinatal risk (1.14; 1.05-1.25). For multiparae, each five-year increase in age beyond 35 years was independently associated with adverse maternal (1.23; 1.09-1.39) and perinatal outcomes (1.23; 1.09-1.39). CONCLUSIONS: For women aged ≥35 years, presence of medical conditions conferred a greater risk for morbidity/mortality than age itself. For multiparous women, the effects of medical and obstetric history were additive. The contribution of maternal age to adverse outcomes in pregnancies without significant medical and obstetric history is modest.