Koenigsfeld, Germany

An Extension Study to Assess Long-Term Safety of Eplontersen in Adults With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)

This is a multicenter, open-label, Phase 3 study in up to approximately 1400 participants. Eligible participants will receive eplontersen once every 4 weeks for up to 36 months or 6 months after eplontersen is approved and available in the site's country, whichever occurs first. Participants will also receive daily supplemental doses of the recommended daily allowance (RDA) of vitamin A. This study will consist of the following periods: less than or equal to (≤) 10-week screening assessment period, up to 36-month treatment period, and up to 6-month post-treatment evaluation period.

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.

Staphylococcus Aureus Network Adaptive Platform Trial

Infection of the bloodstream with the bacterium Staphylococcus aureus (Staphylococcus aureus bacteraemia, SAB) is a serious infection that results in 15-30% of affected patients dying within three months of acquiring the infection. Treatment of this infection requires patients to be hospitalised, treated with prolonged antibiotics through an intravenous line, and carefully examined for the occurrence of complications associated with this condition. At present, there are many treatment options in current use, with no clear agreement as to which of these is best. The SNAP trial aims to identify which treatment options for SAB results in the fewest patients dying within the first 90 days after an infection. In contrast to a conventional clinical trial, the SNAP trial will examine multiple different treatment options at once. Patients will be randomly assigned to different concurrent treatment options currently considered acceptable in routine medical care, but as the trial progresses, more patients will be assigned to treatments that appear to have better outcomes than those with worse outcomes. The trial will adapt to accumulating trial evidence, on a regular basis, by removing treatment options found to be inferior, incorporating new treatment options, and ensuring that all patients in the trial receive the best treatments once they have been identified. Over time, we hope to determine the best combination of treatment options for patients with SAB. The SNAP Trial infrastructure will also support a number of sub-studies. A list of all active sub-studies can be found on the SNAP website: https://www.snaptrial.com.au/substudies.

Sentinel Node Biopsy in Endometrial Cancer

Hypothesis: The primary hypothesis is that SNB will not cause detriment to patients (lymphoedema, morbidity, loss of quality of life) and not increase costs compared to patients without a retroperitoneal node dissection. The secondary hypothesis is that disease-free survival in patients without retroperitoneal node dissection is not inferior to those receiving SNB. Aims: To determine the value of SNB for patients, the healthcare system and to exclude detriment to patients. Objectives: Primary Stage 1: To determine the recovery of participants (defined as incidence of adverse events, lower limb lymphoedema and health-related QOL) and to the healthcare system (cost) of Sentinel Node Biopsy (SNB) for the surgical treatment of endometrial cancer. Primary Stage 2: Compare disease-free survival at 4.5 years for participants randomised to receive hysterectomy, bilateral salpingo-oophorectomy with SNB compared to participants randomised to hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection. Secondary: - Compare patterns of recurrence and overall survival (OS) between the groups - Determine the cost-effectiveness of SNB - Compare Patient Reported Outcomes (PROMS) between the groups at 12 months from surgery - Compare Health Related Quality of Life (HRQL) and Fear of Recurrence between the groups at 12 months from surgery - Compare perioperative outcomes (duration of surgery, length of hospital stay, intraoperative blood loss, blood transfusion requirements) and the incidence of intra- and postoperative adverse events within 12 months from surgery between the groups - Compare lower limb lymphoedema at 12 months after surgery - Compare the need for postoperative (adjuvant) treatments between groups - Determine the impact of body composition and frailty on survival, quality of life, lymphoedema, peri-, intra- and postoperative outcomes - Compare follow-up strategies (clinical vs symptom checklist) - Translational Research - Trans-ENDO 3 - biobanking strategy - Compare the Molecular profile at 12 months from surgery between the groups

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.

Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

Patients are stratified into 4 early risk groups for therapy during the consolidation phase (T/early SR, T/early non-SR, pB/early non-HR, pB/early HR) and 5 risk groups for post-consolidation therapy (T/non-HR, T/HR, pB/SR, pB/MR, pB/HR). Risk stratification is based on immunophenotypic lineage, genetics of leukemic cells and treatment response on the basis of cytomorphology and methods for detection minimal residual disease. The trial includes four randomized study questions testing experimental treatments on top of the risk-stratified standard chemotherapy backbone: Primary study questions: Randomization R-eHR: Early High-risk (early HR) pB-ALL defined by genetics and/or inadequate treatment response over the course of induction: Can the probability of event-free survival (pEFS) from time of randomization be improved by additional therapy with the proteasome inhibitor bortezomib during an extended consolidation treatment phase compared with standard extended consolidation? Randomization R-HR: High-risk (HR) pB-ALL defined by genetics and/or inadequate treatment response by the end of consolidation: Can the pEFS from time of randomization be improved by a treatment concept including two cycles of post-consolidation immunotherapy with blinatumomab (15 µg/m²/d for 28 days per cycle) plus 4 doses intrathecal Methotrexate replacing two conventional highly intensive chemotherapy courses? Randomization R-MR: Intermediate risk (MR) pB-ALL defined by genetics and intermediate MRD response: Can the probability of disease-free survival (pDFS) from time of randomization be improved by additional therapy with one cycle of post-reintensification immunotherapy with blinatumomab (15 µg/m²/d for 28 days)? Randomization R-T: Early non-standard risk (early non-SR) T-ALL patients defined by treatment response over the course of induction: Can the pEFS from time of randomization be improved by the extension of the standard of care consolidation phase by 14 days with an increase of the consolidation cumulative doses of Cyclophosphamide, Cytarabine and 6-Mercaptopurine by 50%? Secondary study questions: All randomizations: Can the overall survival be improved by the treatment in the experimental arm? All randomizations: What is the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm? Randomization R-eHR: Can the MRD load after consolidation treatment be reduced by the additional treatment with bortezomib? Randomization R-HR: Can treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment be reduced when replacing two intensive chemotherapy courses by two cycles of immunotherapy with blinatumomab? Randomization R-HR: What is the proportion of patients with insufficient MRD response to blinatumomab as defined in the protocol as compared to the MRD response after the HR-2' block in the control arm? Randomization R-HR: Can the MRD load after the first treatment cycle (HR 2'/blinatumomab) and the second cycle (HR-3'/blinatumomab) be reduced in the experimental arm when compared with conventional intensive chemotherapy? Randomization R-MR: What is the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the blinatumomab cycle compared to 4 weeks of standard maintenance therapy? Randomization R-T: Can the MRD load after consolidation treatment be reduced by extension of the consolidation phase? Standard-risk patients: Is the clinical outcome comparable to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009? A small subgroup of patients at very high relapse risk is eligible for allogeneic hematopoietic stem cell transplantation after the intensified consolidation therapy phase. Patients with T-ALL and hyperleukocytosis (>=100,000/µL) and patients with CNS involvement at diagnosis (CNS3 status) are eligible for cranial irradiation with 12 Gy if age at time of irradiation is at least 4 years.

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

A Study Evaluating the Efficacy and Safety of Adjuvant Giredestrant Compared With Physician's Choice of Adjuvant Endocrine Monotherapy in Participants With Estrogen Receptor-Positive, HER2-Negative Early Breast Cancer (lidERA Breast Cancer)

Long Term Evaluation of Safety and Efficacy of Tildrakizumab in Patients With Psoriatic Arthritis

Subjects from both INSPIRE 1 (TILD-19-07) and INSPIRE 2 (TILD-19-19) studies to roll over into this INSPIRE LTE study (TILD-21-01).

Long-term Outcomes of Lidocaine Infusions for Post-Operative Pain (LOLIPOP) Trial

The Trial's purpose is to evaluate the effectiveness of lidocaine infusions commenced during surgery and extending up to 24 hours postoperatively, on the incidence of moderate or severe chronic post-surgical pain (CPSP) detected one year following surgery in female patients undergoing elective breast cancer surgery. The trial has 90% power to detect a clinically meaningful (25%) reduction in the incidence of the primary outcome. Secondary outcomes include safety events, analgesic efficacy (pain scores and opioid consumption), neuropathic characteristics of CPSP, and psychological and quality of life outcomes.