Canberra, Australia

A Trial to Treat Polyomavirus Infections (BKPyV) in Kidney and Simultaneous Kidney Pancreas Transplant Recipients

BKPyV infection is a rare but also devastating disease in kidney and SPK transplant recipients. Immunosuppression used in transplantation minimises the risk of acute rejection and eventual graft loss, but suppression of the immune system increases the risk of opportunistic infections and reactivation of latent viruses causing disease, such as BKPyV infection. Therefore, balancing the complications of excessive versus inadequate immunosuppression is a key priority for patients and health professionals. The BEAT-BK trial is designed through a structured, consensus process, and informed by the pilot observational data generated by the investigators. The conventional immunosuppression reduction approach may include judicious reduction in the doses of calcineurin inhibitors and anti-proliferative agents, or conversion to less potent immunosuppression therapy such as a switch from tacrolimus to cyclosporine, or mycophenolate to azathioprine. While adjuvant therapy is not commonly used, 63% of participants would consider IVIG as a 'rescue', when conventional therapy has failed, or the graft function is deteriorating rapidly. IVIG is a nondepleting agent containing natural antibodies with potential antiviral and immunomodulatory properties. It is used against some chronic infections (Epstein-Barr virus) and the treatment of antibody-mediated rejection in kidney transplantation. In BKPyV infection, the certainty of the evidence for IVIG is very low due to imprecision, and high risk of bias (small, case series, retrospective cohorts), but it holds promise based on findings from our observational data (n = 50). Recipients with BKPyV-DNAemia who received IVIG as adjuvant therapy were more likely to achieve complete viral clearance at 12 months (77.3% vs. 33.3%, p < 0.01) and less likely to relapse (11% vs. 27.3%, p=0.01) compared to recipients who received conventional therapy alone.

The National Australian HCV Point-of-Care Testing Program

The advent of simple direct-acting antiviral hepatitis C (HCV) therapies with cure rates >95% is one of the greatest medical advances in decades, having led to a reversal in liver-related mortality. In Australia, treatment uptake has declined between 2016 (32,000 treated) and 2019/20 (2019: 11,500; 2020: 8,500).1 Progress towards HCV elimination has been impeded by COVID-19, affecting the delivery of national and state-based HCV strategies. Improving HCV treatment uptake to reduce disease burden is a key aim of global, national and state-based HCV strategies.2-4 Scale-up of HCV testing and treatment will be required to achieve elimination by 2030. Current diagnostic pathways require multiple visits to a practitioner reducing the proportion who receive a diagnosis. In Australia, 81% of people have had HCV antibody testing (indicates exposure), but only 47% have been HCV RNA tested (indicates active infection and the need for HCV treatment).5 Mathematical modelling suggests that HCV RNA testing needs to increase by at least 50% annually to achieve elimination in Australia by 2030.6 The Kirby Institute is an international leader in research evaluating the Xpert HCV assay (Grebely Lancet Gastro Hep 2017), having built a large network of Xpert platforms for HCV testing in needle and syringe programs, prisons, drug treatment clinics, tertiary hospitals, and Aboriginal Community Controlled Health Service. In Kirby-led research, point-of-care HCV testing interventions in needle and syringe programs and prisons have resulted in high HCV treatment uptake (70-90%). The Kirby Institute and Flinders University also have a strong track record of implementing point-of-care testing for STIs and COVID-19, providing an ideal foundation to scale-up Xpert HCV testing in Australia. The Kirby Institute and Flinders University will establish the Australian National HCV Point-of-care Testing Program for the scale-up of point-of-care HCV RNA testing in services with high prevalence of HCV infection, including community health centres, drug treatment clinics, needle and syringe programs, and prisons. This program will include the development of standard operating procedures, logistics/deployment, initial set-up, an operator training program, and quality assurance and competency assessment program. An observational cohort study that will be established to evaluate HCV treatment uptake following scale-up of point-of-care HCV testing among people with a risk factor for acquisition of HCV infection or people attending a service caring for people with risk factors for the acquisition of HCV infection. This study will also include the linkage of survey data to a range of administrative datasets which will be used to evaluate the impact of HCV testing and treatment scale-up on a range of long-term health outcomes. Participants will be recruited from settings that provide services to people with a risk factor for the acquisition of HCV infection. Participants will attend a single visit to receive point-of-care HCV testing and complete a self-administered survey. Testing will be performed using point-of-care HCV antibody testing (results within 1-20 minutes, depending on the test) and if positive, HCV RNA testing will be performed. Participants who have previously had HCV infection or previously received HCV treatment will be tested using point-of-care HCV RNA testing. Participants will not receive treatment as a part of this study. Participants who are HCV RNA detectable will be linked to standard of care for any other clinical assessments and treatment initiation.

Polysomnographic Titration of Non-invasive Ventilation in Motor Neurone Disease

Non-invasive ventilation (NIV) is a treatment that uses positive pressure delivered via a face mask or mouthpiece to assist a person to breathe. It can be used as a long-term treatment for people whose breathing is failing - usually due to chronic conditions that produce weakness of the respiratory muscles such as motor neurone disease / amyotrophic lateral sclerosis [MND/ALS]chronic obstructive pulmonary disease). Most people with MND/ALS use NIV at night initially. Even though NIV may improve survival and function, many are unable to use it for more than 4 hours per day (which is considered a threshold amount of use in order to gain a benefit) and many others are unable to tolerate it at all. Our team has recently provided evidence that specific and individualised titration of NIV leads to better outcomes in people with MND. This previous trial determined that the use of a sleep study (also called 'polysomnography') can improve the way people are initially set up with NIV. This study will replicate and extend the single site study in a large, multi-centre randomised controlled trial (RCT) across multiple sites This multi-centre RCT will also include a 12-month follow-up period to evaluate longer-term outcomes.

Investigating the Utilisation and Effectiveness of Originator and Biosimilar Anti-TNF Agents

Observation of Clinical Routine Care for Heart Failure Patients Implanted With BIOTRONIK CRT Devices

Study Evaluating the Efficacy of Maintenance Olaparib and Cediranib or Olaparib Alone in Ovarian Cancer Patients

ICON9 is an international multicentre randomised, phase III trial assessing maintenance treatment with olaparib and cediranib or olaparib alone in women with relapsed ovarian cancer whose disease progressed more than 6 months after first line chemotherapy. Women whose disease responds to platinum chemotherapy following 3 to 4 cycles can be registered for collection of germline BRCA test results if known, and somatic BRCA testing of archival tumour specimens or secondary debulking tissue if required. Patients who have completed treatment and whose disease has responded (partial or complete) to a minimum of 4 cycles of platinum based chemotherapy will be randomised to maintenance treatment of either olaparib and cediranib or olaparib alone. The maintenance regimen may be continued beyond radiological progression until trial closure if the patient is deemed to still be deriving clinical benefit, but must be discontinued once subsequent treatment is instituted.

The EXCEL Registry of Patients Requiring ECMO

The aim of EXCEL is to generate a bi-national multidisciplinary network of integrated care for patients suffering acute cardiac or respiratory failure or cardiac arrest requiring extracorporeal membrane oxygenation (ECMO) to monitor long term outcomes and identify best practice. Each year around 130,000 Australians and New Zealanders are admitted to an intensive care unit (ICU). The sickest patients in the ICU who have severe failure of the heart or lungs may require an external machine to oxygenate their blood in addition to a mechanical ventilator. This intervention, called extracorporeal membrane oxygenation (ECMO), involves circulating all of the patient's blood through large cannulae to external machinery every minute. It has the capability of completely replacing a non-functioning heart or lungs for days to weeks on end. These critically ill patients who require ECMO are the sickest in the hospital with only 42% hospital survival. The use of ECMO has doubled in Australia and New Zealand and globally over five years, and in the USA has increased by 433%. The use of ECMO is associated with significant costs and risks, and it requires specialist training and expertise. In order to prepare for the organisation of these complex interventions in the ICU across regions, the investigators need to have accurate data on patients undergoing ECMO. The investigators monitor and review current practice in ECMO services by providing robust binational registry data to service providers and clinicians with a closed-loop feedback system. EXCEL explores barriers and enablers to evidence-based care in ECMO services and providing a platform to embed clinical trials. The investigators will translate findings with greater capacity, reach, and impact to drive measureable change in practice and improve patient-centred outcomes. The EXCEL Partnership represents a novel, coordinated effort to create a high-quality, detailed, prospective registry of patients requiring ECMO at ECMO centres. A tailored, detailed ECMO registry (EXCEL) can be used to address specific safety concerns, clinical questions and process of care issues. As a result, EXCEL can be designed and implemented to answer new investigator-initiated, hypothesis-driven clinical questions.

EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer

Radiation therapy (RT) after breast conserving surgery to improve local control and survival is the current standard of care for patients with early breast cancer. However, breast cancer is a heterogeneous disease, and the absolute benefit of RT in individual patients varies substantially. Thus, a pressing priority in contemporary breast cancer management is to tailor RT utilisation to the individual recurrence risks by identifying patients who are unlikely to benefit from RT, thereby avoiding the morbidity and costs of over-treatment. It is recognised that selected patients with early breast cancer are unlikely to derive benefits from RT after breast conserving surgery. However, randomised trials have not consistently identified patients who may safely omit RT using conventional clinical-pathologic characteristics. Breast cancer intrinsic subtypes distinguished by gene expression profiling are shown to be associated with distinct clinical outcomes. There is substantial evidence supporting the clinical validity of multigene assays including the PAM50-based Prosigna Assay that identifies intrinsic subtypes and generates a Risk of Recurrence score (ROR) to quantify individual risks of distant relapse. Multigene assays are increasingly integrated into clinical practice to inform chemotherapy decision, highlighting their substantial practice changing potential in personalising the use of RT for early breast cancer. A recent analysis of archived tumour specimens of 1,308 patients with early breast cancer has shown significant associations between local recurrence risk and the PAM50-defined intrinsic subtypes and ROR score. EXPERT presents a unique opportunity of clinical and public health importance to optimise personalised local therapy for early breast cancer through precise, individualised quantification of local recurrence risk to identify low-risk patients for whom RT after breast conserving surgery may be safely omitted.

Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia

Community-acquired pneumonia (CAP) that is of sufficient severity to require admission to an intensive care unit (ICU) is associated with substantial mortality. Patients with pneumonia who are being treated in an ICU will receive therapy that consists of many different treatments, as many as 20 or 30. These treatments act together to treat both the infection and its effects on the body. When treating a patient, doctors choose from many different treatments, most of which are known or believed to be safe and effective. However, doctors don't always know which treatment option is the better one, as individuals or groups of individuals may respond differently. This study aims to help doctors understand which treatments work best. This clinical study has been designed in a way that allows the information from patients already in the study to help new patients joining the study. Most studies aren't able to do that. REMAP-CAP has been designed to: - Evaluate multiple treatment strategies, at the same time, in the same patient. - Reach platform conclusions when sufficient data is accrued, rather than when a pre-specified sample size is reached - Utilise data that is already accrued to increase the likelihood that patients within the trial are randomised to treatments that are more likely to be beneficial - New questions can be substituted into the trial as initial questions are answered, meaning that the trial can be perpetual or open-ended - Interactions between interventions in different domains can be evaluated It is reasonable to presume that any pandemic respiratory infection of major significance to public health will manifest as life-threatening respiratory infection including Severe Acute Respiratory illness and severe Community Acquired Pneumonia (CAP) with concomitant admission to hospital, and for some patients, admission to an Intensive Care Unit (ICU). Previous pandemics and more localized outbreaks of respiratory emerging infections have resulted in severe CAP and ICU admission. Previous pandemics and outbreaks of emerging infectious diseases have outlined the urgent need for evidence, preferably from Randomized Controlled Trials (RCTs), to guide best treatment. However, there are substantial challenges associated with being able to organize such trials when the time of onset of a pandemic and its exact nature are unpredictable. As an adaptive platform trial that enrolls patients during the interpandemic period, REMAP-CAP is ideally positioned to adapt, in the event of a respiratory pandemic, to evaluate existing treatments as well as novel approaches.

Randomised Evaluation of Sodium Dialysate Levels on Vascular Events

RESOLVE is a pragmatic, cluster-randomised, open-label study designed to evaluate in real-world conditions the comparative effectiveness of two default dialysate sodium concentrations. Dialysis sites will be randomised in a 1:1 ratio to a default dialysate sodium concentration of 137mmol/l or 140mmol/l. 'Default' is defined as the use of the allocated dialysate sodium for ≥ 90% of delivered dialysis sessions in the unit. All other care will be according to standard local practices as determined by the site. Outcomes will be assessed on individual patients dialysing at those sites. Sites will be asked to consent to participation while waiver or opt-out consent will be sought for individual patients. It is anticipated that site accrual will occur over 5-7 years with average study duration expected to be approximately 2-5 years. The actual length of the study will be end-point determined.