Chichester, United Kingdom

A Study to Evaluate the Safety and Efficacy of FB102 in Patients With Non-segmental Vitiligo

Approximately 16 participants who meet all the screening eligibility criteria will be randomized to receive FB102 or placebo.

Pilot Study of the Coronary Spur Stent for In-stent Restenosis (DEEPER CORONARY)

Fluid Administration and Fluid Accumulation in the Intensive Care Unit

Background: Fluid accumulation is associated with adverse outcome in ICU patients, however, assessment of fluid status is often difficult and no established definition and consistent detection method exists. Former research has primarily focused on the use of resuscitation fluid, but a substantial amount of fluid is administered throughout the entire ICU stay and this fluid may be a clinically relevant source of fluid accumulation. Objectives: To describe fluid administration practices during the entire ICU stay, and provide contemporary epidemiological data on fluid accumulation, fluid removal, risk factors and association with patient outcomes from a worldwide perspective. Study design: International inception cohort study. Patients will be included during a 14-day inception period to be chosen by each participating site. Population: Critically ill adult patients (≥ 18 years) with acute admission to the ICU. Intervention: None. Only routinely available data will be collected. Study duration: Patients are followed daily until ICU discharge or death for a maximum of 28 days. Follow-up is performed 90 days after ICU admission.

Stepcare Extended Follow-up Substudy

This extended follow-up substudy is incorporated into the multi-center, international, factorial randomized Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation -STEPCARE trial (Clinical trials identifier:NCT05564754) were out of hospital cardiac arrest participants will be randomized to different targets of sedation, temperature, and MAP management. Only selected STEPCARE sites will participate in this extended follow-up substudy. At the extended follow up participating sites all out of hospital cardiac arrest participants randomized in the STEPCARE trial, who survive and provide consent, will be eligible to participate in this substudy, with no further inclusion or exclusion criteria.The extended follow-up substudy is estimated to enroll approximately 600 post OHCA survivors. One nominated caregiver per post OHCA survivor will be invited to be included in the study. Participants will be followed up at 6 and 12 months. The primary outcome for this extended follow up substudy is cognitive function at 6 months for the out of hospital cardiac arrest survivors andCaregiver burden at 6 months for the caregivers.

SODium BICarbonate for Metabolic Acidosis in the ICU

Background: Metabolic acidosis refers to any process that elevates the concentration of hydrogen ions in the body, and is commonly encountered in critical illness. Lactic acidosis, diabetic ketoacidosis, and hyperchloremic acidosis are major examples seen in the intensive care unit (ICU). Metabolic acidosis may impair cardiac function, and sodium bicarbonate can be used to normalise blood pH. Despite being in common clinical usage, the clinical efficacy of sodium bicarbonate is still uncertain. Previous studies exploring the effects of sodium bicarbonate therapy have been limited and of variable quality. Aim: This trial aims to assess if, among adults in the ICU with metabolic acidosis, an infusion of sodium bicarbonate diluted in 5% dextrose, compared with an infusion of 5% dextrose, reduces Major Adverse Kidney Events within 30 days of randomization. Study Design: Phase 3, international, multicentre, double-blind, randomised clinical trial. Participants: Adult patients (≥ 18 years old), admitted to the ICU within 48 hours, receiving a continuous infusion of a vasopressor drug to maintain a mean arterial pressure > 65 mmHg (or a mean arterial pressure target set by the treating clinician), a dedicated line (central or peripheral) is available (or is about to be made available within 1 hour after randomisation), and within two hours prior to randomisation the participant has metabolic acidosis, defined as: 1) pH < 7.30; 2) BE ≤ -4 mEq/L; and 3) PaCO2 ≤ 45 mmHg for non-intubated patients or PaCO2 ≤ 50 mmHg for non-intubated patients Intervention: Patients will be randomly allocated in a 1:1 ratio to receive two treatments that are commonly used either an infusion of 5% dextrose (D5W) + sodium bicarbonate, or D5W alone, as a comparator. Study drug will be continuously infused targeting a pH 7.30 - 7.35 and a BE ≥ 0 mEq/L. The infusion will be maintained until this target is achieved and continued by titration thereafter for a maximum of 5 hours (to maintain target pH and base excess levels). All other aspects of care will be determined by the treating clinical team, including the use of additional fluid therapy, vasopressors, and other organ support modalities. Open-label sodium bicarbonate bolus infusion is allowed in both groups if clinically indicated. Primary outcome: The primary outcome is the proportion of patients who meet one or more criteria for a major adverse kidney event within 30 days (MAKE 30). MAKE 30 is a composite of death, new receipt of renal-replacement therapy, or persistent renal dysfunction (defined as a final inpatient creatinine value ≥ 200% of the baseline value). All components of MAKE30 will be censored at hospital discharge or 30 days after enrolment, whichever comes first.

Antenatal Melatonin Supplementation for Neuroprotection in Fetal Growth Restriction

Following detection of FGR, current goals in clinical care center on assessment of fetal wellbeing and evidence of a physiological adaption to placental insufficiency. This information guides the timing of steroids, if indicated, and planning of delivery to minimise the likelihood of stillbirth. Magnesium sulphate is the only available therapy shown to improve fetal brain development in the setting of placental insufficiency and hypoxia. Magnesium sulphate works through reducing glutamate release in a hypoxic environment, likely minimising hypoxic brain injury. It appears to reduce the risk of subsequent cerebral palsy by approximately 30%. However, magnesium sulphate is only used in the hours immediately before birth, while a significant proportion of underlying brain injury in FGR probably occurs over the preceding days to weeks. The use of a safe, maternally administered supplement commenced in the weeks prior to birth could provide further significant benefits in reducing the complications faced by premature infants in the setting of placental insufficiency. Melatonin (5-methoxy-N-acetyltryptamine) is an endogenous lipid-soluble hormone produced primarily by the pineal gland in humans. It provides circadian and seasonal timing cues due to neuroendocrine control in response to daylight. As such, melatonin secretion is relatively low during the daytime, with an exponential increase in synthesis and secretion occurring from mid-afternoon and peaking at midnight. In addition to timing cues, melatonin is a powerful antioxidant, acting both as a direct scavenger of oxygen free radicals, especially the highly damaging hydroxyl radical, and indirectly via up-regulation of antioxidant enzymes including glutathione peroxidase, glutathione-reductase, superoxide dismutase and catalase. The metabolites of melatonin provide further anti-oxidant effect. Melatonin is an appealing treatment for use as a fetal neuroprotectant in pregnancy, as it freely crosses the placenta and blood-brain barrier. It also has an excellent safety profile with no known adverse effects. Placentae express receptors for melatonin, and thus melatonin may protect against oxidative stress generated by ischaemia-reperfusion injury of the placenta. Melatonin has been studied in several clinical trials related to human reproduction and for different purposes. However, no randomized trial assessing the role of melatonin in fetal neuroprotection has been completed. Melatonin has been evaluated in assisted reproductive technology where the quality of oocytes is vital for the success of in-vitro fertilization (IVF). Melatonin and myo-inositol are two compounds found in the follicular fluid that are important for oocyte maturation and quality. Tamura et al. (in 2008) and Rizzo et al. (in 2010) conducted clinical studies where they co-treated patients with 2milligram (mg) and 3mg melatonin respectively. The patients in the Tamura et al. study were given melatonin from the fifth day of the previous menstrual cycle until the day of oocyte retrieval. Both studies revealed improved oocyte quality, but the tendency to increase pregnancy rates failed to reach statistical significance. A study conducted by Unfer et al. in 2011 administered 2g myo-inositol, 200µg folic acid plus 3mg melatonin per day for 3-months to women who failed to become pregnant in previous IVF cycles, at the commencement of a new IVF cycle. This treatment resulted in a total of 13 pregnancies, 9 of which were confirmed ultrasonographically and 4 undergoing spontaneous abortion. Treatment continued after completion of the IVF cycle, throughout pregnancy until delivery. Treatment was associated with better quality oocytes and more successful pregnancies. All babies that were born from melatonin-treated pregnancies were in healthy condition with no abnormalities. To evaluate the maternal-fetal transfer of melatonin a study by Okatani et al. in 1998 administered a single oral dose of 3mg melatonin to 33 women at term (37-40 weeks gestation) 1- to 4-hours before a planned caesarean section. Levels of melatonin were evaluated in maternal venous blood and umbilical venous and arterial blood. A total of 12 healthy pregnant women delivered by vaginal birth served as controls. Administration of melatonin led to a rapid (<120 minutes) and marked (>20-fold) increase in the fetal serum levels. There were no differences between maternal and fetal serum levels of melatonin, suggesting a rapid and unrestricted transfer of melatonin from mother to fetus. The same investigators tested whether melatonin could up-regulate antioxidant enzymes. No longer than 12 hours before voluntary termination of pregnancy (between 7- and 9-weeks gestation), an oral dose of 6mg melatonin was administered to 47 pregnant women. A significant increase of the antioxidant enzyme glutathione peroxidase was observed in chorionic homogenates derived after the procedure, leading to the conclusion that melatonin might provide an indirect protection against injury caused by reactive oxygen species as seen in preeclampsia, FGR and fetal hypoxia. The dose used in this trial is based on data from a clinical trial of melatonin for preeclampsia showing that 30mg per day was safe for mother and baby without any apparent adverse effects. Venous cord blood concentrations of melatonin achieved were unchanged between a mother receiving 8mg and 30mg per day of melatonin (melatonin concentration ~2100pg/mL). This cord blood concentration would appear sufficient for neuroprotection according to information in sheep models. However, the degree of oxidative stress reduction achieved within the placental bed was less in mothers receiving 8mg melatonin per day. As such, it was felt that the higher dose of 30mg per day was more likely to achieve a clinically significant result. The investigating team has shown that melatonin supplementation exerts multiple anti-oxidant and anti-inflammatory effects, leading to a significant reduction in oxidative stress and lipid peroxidation within the fetal brain in an ovine model of FGR. In the absence of melatonin, this study showed that lipid peroxidation within the fetal brain led to significant white matter hypomyelination and axonal injury, causing impaired neurological performance in the lambs. Injury was ameliorated entirely in those exposed to melatonin supplementation, with no structural brain injury seen and neurodevelopmental outcomes normalised. As a result, a small (n=12) phase 1 trial was conducted at Monash Health supplementing pregnancies affected by severe FGR with 8mg of melatonin per day. Melatonin use was well tolerated with no adverse effects seen. A reduction in the degree of placental lipid peroxidation was seen (n=6). Early-onset FGR carries significant fetal risks of premature birth. Following diagnosis, those babies requiring delivery <32 weeks gestation carry approximately an 8% risk of stillbirth or neonatal death, with those born <28 weeks gestation having a significantly higher perinatal mortality rate. Around 30% of survivors will suffer serious neonatal morbidity. Furthermore, 8% are found to have neurodevelopmental impairment at two years of life. These numbers are likely to be an underrepresentation as they are from a trial population, which was closely surveyed compared to the general population. With approximately 97% of FGR infants born <32 weeks delivered by caesarean section, the mother of a preterm FGR fetus faces the risks associated with morbidity and mortality relating to caesarean birth. Furthermore, the mother also faces a significant risk of morbidity and mortality from pre-eclampsia, which develops among 15 - 40% of women who have a growth-restricted fetus. The most common side effects of melatonin are headache, dizziness, nausea and sleepiness. Melatonin does not have any acute pharmacological effects on the nervous or vascular systems, apart from its benign but active impact on sleep mechanisms. Extremely high doses of up to 800mg/kg of melatonin were safely administered to animals without deaths, meaning a median lethal dose could not be established. In humans, long-term treatment with high, daily doses of up to 10g melatonin did not cause any toxicity except for isolated cases of cutaneous flushing, abdominal cramps, diarrhoea, scotoma lucidum and migraine. Prolonged ingestion of 1g melatonin per day caused only subjective drowsiness but did not provoke any toxicity in the eyes, liver, kidneys and bone marrow. In a phase II clinical trial conducted in the Netherlands, 1400 women were given 75mg melatonin nightly over 4-years, with no side effects reported. The safety of melatonin use in pregnancy was explored in early pregnant Sprague-Dawley rats, at doses ranging from 1 to 200mg/kg/day and did not affect antenatal mortality, fetal body weight or other measures of fetal wellbeing. Maternal adverse effects seen at high doses, included mild sedation, reduced maternal weight gain and reduced food intake. This study sought to determine the maternal and fetal no adverse effect level (NOAEL). The NOAEL is the exposure level where a particular substance does not statistically or biologically significantly increase the frequency or severity of adverse effects in an exposed population compared to a suitable control population. The maternal NOAEL in this study was found to be 100mg/kg/day, the fetal NOAEL was established at ≥200mg/kg/day when administered to the mother. The maternal lowest observed adverse effect level toxicity was 200mg/kg/day. With the above information taken in context, the Australian Therapeutic Goods Administration (TGA) has assigned melatonin a Pregnancy Category B3 classification. The investigators have recently completed a phase 1 trial (NCT01695070) using melatonin supplementation in pregnancy, as well as a clinical trial in women with pre-eclampsia (ACTRN12613000476730) using the same dose as proposed for this trial, and to date no adverse effects have been identified in the mother, fetus or neonate. PROTECT Me aims to be a multicentre, triple-blinded, randomized, parallel group, placebo controlled trial. This trial will be undertaken and co-ordinated by Monash Health. Other perinatal hospitals across Australia and New Zealand have agreed to join the trial so far. Each centre will nominate a local investigator +/- a researcher to oversee local recruitment. The required sample size has been calculated to detect if melatonin supplementation affords a clinically relevant difference in neurodevelopmental outcomes among survivors. An increase of 4-5 quotient points in the Bayley-IV Cognitive scale has been deemed sufficiently clinically meaningful to drive changes in health policy previously. Power analysis shows that 69 participants per group will allow the detection of a difference in the Bayley-IV cognitive score of 5 points between the two groups, with a power of 90% and an alpha level of 0.05, using 2 sided T test for comparison. This assumes a standard deviation of 9 and that, on average, the growth restricted infant has been shown to have a cognitive score 5 points lower than the healthy preterm infant and 8 points lower than the healthy term infant. Typically, the Bayley IV score has a standard deviation of 15, however reduced variability has been seen in the FGR population and this has informed the standard deviation used here. Among pregnancies complicated by early onset FGR a perinatal loss rate of ~15% is commonly observed. Allowing for a perinatal loss rate of 15%, an extra 44 women will be recruited. Assuming an additional 5% loss to follow-up rate, the investigators will aim to recruit an extra 14 participants. This trial also aims to assess whether the impact of melatonin is different at different gestational ages. Therefore, a sub-analysis will be undertaken to compare those with early onset FGR identified <28 weeks' gestation to those with late-onset FGR identified between 28-31+6 weeks gestation. To ensure that this sub-analysis is adequately powered, participants recruited will be randomized to either melatonin or placebo based on their gestational age at diagnosis. Therefore, recruiting 84 participants per group will see the overall trial aiming to recruit 336 participants.

Shock Energy for Electrical Cardioversion of Persistent Atrial Fibrillation

Atrial fibrillation is the world's most common arrhythmia, with an incidence that is increasing in Western countries. One-in-four adults will experience atrial fibrillation at some point in their life. Strategies for the management of atrial fibrillation include rate control, prophylaxis against stroke, lifestyle modification, and restoration of sinus rhythm through medical or electrical cardioversion. Electrical cardioversion for the restoration of sinus rhythm was first described by Lown and colleagues in 1962, and has undergone a number of procedural advances in the intervening six decades. Chief amongst these was a transition from cardioverting using monophasic to biphasic waveforms, something unequivocally demonstrated to increase cardioversion success, with lower energy, current, and less skin and muscle damage than monophasic devices. Yet the majority of the data which continues to guide cardioversion is derived from the era of monophasic therapy. Data from cardioversion with monophasic waveforms suggests that the use of higher initial shock energy is associated with higher first shock success, fewer shocks, and lower levels of skeletal muscle injury, with no increase in troponin to suggest greater cardiac injury. Likewise, studies of shock energy using biphasic devices have demonstrated benefit of maximum fixed shock energy. However, whilst the energy of a defibrillator remains entrenched in the descriptive vocabulary of cardioversion for atrial fibrillation, it is the flow of current across the myocardium that achieves cardioversion, and resuscitation guidelines have previously recommended a switch to the more physiologic current-based description. Different defibrillators deliver different currents at the same energy setting based on the capacitance of the device. As such, manufacturers of defibrillators recommend different energy levels for cardioverting atrial fibrillation with some standard biphasic defibrillators (Philips HeartStart MRx Monitor/Defibrillator) unable to deliver higher than 200J energy, while some (Lifepak 15 Monitor/Defibrillator) extend to 360J. No studies have compared initial 200J vs. 360J shock energies between these devices for cardioverting persistent atrial fibrillation. This study is a single centre randomized non-blinded study of the effectiveness of 200J vs. 360J fixed output biphasic electrical cardioversion in patients undergoing electrical cardioversion of persistent atrial fibrillation. The study hypothesis is that cardioversion with shock energy fixed to 360J delivered by a LifePak Monitor/Defibrillator is more efficacious than a 200J delivered by a Philips HeartStart MRx Monitor/Defibrillator, without worsening safety outcomes.

CORE-OLE: A Study of Olezarsen (ISIS 678354) Administered Subcutaneously to Participants With Severe Hypertriglyceridemia (SHTG)

This is a multi-center, open-label extension (OLE) study of approximately 800 participants with SHTG who would be rolled over from studies ISIS 678354-CS5 (NCT05079919) or ISIS 678354-CS6 (NCT05552326). Day 1 of this study may be same as the Week 53 visit of either ISIS 678354-CS5 or ISIS 678354-CS6, as applicable. Participants will receive olezarsen during the 157-week treatment period. The study will include a 31-day qualification Period, a 157-week treatment period, and a 13-week post-treatment period.

Duration of Cardiac Antimicrobial Prophylaxis Outcomes Study

This trial will evaluate the clinical effectiveness, health-economic outcomes and microbiological impact of intraoperative (only) compared with intraoperative plus postoperative prophylaxis durations in patients undergoing cardiac surgery. CALIPSO, a multicentre, adaptive, double-blind, three-arm, placebo-controlled, phase IV, noninferiority trial will examine the incidence proportion of SSI following cardiac surgery. Our three-intervention trial will compare: Arm A Administration of prophylaxis in intraoperative period only Arm B Administration of prophylaxis in intraoperative plus for 24 hours postoperatively Arm C Administration of prophylaxis in intraoperative plus for 48 hours postoperatively

Continuous Temperature Monitoring for tHe Early Recognition of Febrile Neutropenia in Haematological MALignancies

Patients with haematological malignancies such as leukaemia, lymphoma and myeloma often require intensive treatments such as chemotherapy, stem cell transplantation (either autologous or allogeneic) or CAR T-cell therapy. All these therapies can lead to a period of prolonged neutropenia, or low neutrophils, when they are at very high risk of serious bacterial infections. While other countries use routine prophylactic antibiotics, Australasian practice is to focus on prompt recognition and treatment of infections. There is clear evidence that early recognition and treatment of febrile neutropenia with antibiotics leads to improved outcomes, with each hour delay in antibiotic administration associated with an 18% increase in mortality. Current practice is to detect fevers by both routine and symptom-based intermittent ear thermometer testing, with routine monitoring being approximately every four hours. However, neutropenic patients may not develop symptoms before manifesting a fever, meaning that continuous temperature monitoring could potentially lead to earlier recognition and treatment of febrile neutropenia. This pilot study seeks to determine the feasibility of using two separate continuous skin temperature monitors during intensive treatment for haematological malignancies, in the inpatient and outpatient setting. If feasible, this could be used to increase the amount of treatments that can be safely performed as outpatients, as well as allowing earlier identification and treatment of febrile neutropenia. The two proposed measuring devices are: 1. TempTraq adhesive temperature sensor, a skin temperature sensor which is applied to the axilla for 72 hours, then replaced; and 2. CORE temperature sensor, a rechargeable skin temperature sensor that is attached to the chest with a chest strap. The TempTraq device is an FDA cleared class 2 medical device, while the CORE temperature monitor has received emergency FDA approval as a medical device in the context of the COVID-19 pandemic. If these devices are demonstrated to be feasible, the technology could potentially be used to improve monitoring of immunosuppressed patients out of hospital, allowing patients to receive treatment out of hospital or closer to home. It may also allow earlier detection of febrile neutropenia, and reduce the mortality from this.