N�rnberg, Germany

Sedation, Temperature and Pressure After Cardiac Arrest and Resuscitation

3500 patients who are comatose after cardiac arrest will be included in a trial studying three separate targets. All patients will be randomised to a control or an intervention arm for sedation, temperature and blood pressure targets. These are. 1. Continuous deep sedation for 36 hours or minimal sedation (SEDCARE) 2. Fever management with or without a feedback-controlled device (TEMPCARE) 3. A mean arterial pressure target of >85mmHg or >65mmHg. (MAPCARE) Participants will be followed up at 30 days and 6 months. The primary outcome will be survival at 6 months.

Trial of Venovenous ECMO to De-Sedate, Extubate and Mobilise in Hypoxic Respiratory Failure

Mechanically ventilated patients with moderate to severe acute hypoxic respiratory failure are at increased risk of dying, short and long-term health problems and are often very costly to treat. The mechanical ventilator, whilst often lifesaving, may harm patients in two ways i) directly via damage to the lungs (termed ventilator induced lung injury), and ii) indirectly via paralysis and sedation that patients require to tolerate mechanical ventilation. Paralysis and sedation can increase the risk of secondary infections, weakness, prolonged duration of intensive care, as well as long-term physical disability. There is a need to develop new treatments that support patients and at the same time reduce these complications. Extracorporeal membrane oxygenation (ECMO) is a device that supports the lungs by adding oxygen and removing carbon dioxide from the blood. By providing non pulmonary gas exchange, veno-venous (VV) ECMO can reduce the need for the mechanical ventilator. This in turn can reduce the risk of lung damage, and also removes the need for sedating medications so that activities like physiotherapy can begin earlier. The REDEEM trial is a phase 2, investigator initiated, multicentre randomised controlled trial that will recruit 140 patients with moderate to severe acute hypoxic respiratory failure. It is designed to test whether adding ECMO to the mechanical ventilator, as compared to using the mechanical ventilator on its own, leads to an increase in the number of patients who survive and are discharged earlier from the intensive care unit. If the REDEEM trial confirms adding ECMO is more effective than mechanical ventilation alone, it has the potential to change the current paradigm of intensive care treatment of hypoxic respiratory failure, and could lead to changes in practice globally.

Acute Optic Neuritis Network: an International Study That Invesitages Subjects With a First-ever Episode of Acute Inflammation of the Optic Nerve

The Acute Optic Neuritis Network (ACON) is a global cooperation of currently 26 academic centers longitudinally investigating subjects with inaugural acute optic neuritis (ON). ON often occurs at presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North-American study population, which did not address treatment timing, or antibody serostatus. The ACON study is primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. All patients presenting within 30 days of inaugural ON will be enrolled. For primary analysis, patients will subsequently be assigned either into the MS-ON, aquaporin-4-IgG positive ON (AQP4-IgG+ON) or MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from onset of visual loss to high-dose corticosteroids. The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. Additionally, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include: optical coherence tomography (OCT) and magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4- and MOG-IgG levels; neurofilament; glial fibrillary protein), questionnaires (headache, visual function in daily routine, depression, and quality of life) at presentation, at 6- and 12-months follow-up. Data will be collected from 22 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, Australia and Europe. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and accuracy of diagnostic stratification in acute demyelinating ON.

A Clinical Study to Investigate the Efficacy of Tigilanol Tiglate Directly in Head and Neck Cancer

Primary Objective 1. To evaluate tumour ablation following treatment(s) with intratumoural injections of tigilanol tiglate. Secondary Objectives 1. To assess the safety and tolerability of intratumoural injections with tigilanol tiglate. 2. To evaluate disease control by assessing time to local disease recurrence from last treatment. 3. To evaluate the tumour recurrence rate at injected tumour sites. 4. To evaluate survival by assessing Progression Free Survival (PFS). Exploratory Objectives 1. To assess the impact on Quality of Life (QoL). 2. To assess the degree of wound healing after each treatment. 3. To assess the tumour response in injected and non-injected tumours, based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. 4. To assess the tumour response according to intratumoural Response Evaluation Criteria in Solid Tumours (itRECIST). 5. To assess changes in tumour biomarkers. 6. To assess the tumour microenvironment.

The Willow LTE Study With M5049 in Participants With SCLE, DLE and/or SLE (WILLOW LTE)

ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)

Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS

The primary objective of this study is to establish the maximum tolerated dose of the combination of ASTX727 (decitabine/cedazuridine) and defactinib administered for 5 days of a 28-day cycle in participants with high-risk MDS, low-blast Acute Myeloid Leukaemia (AML), or Chronic Myelomonocytic Leukaemia (CMML). The secondary objectives are to gather in vivo evidence that adjuvant focal adhesion kinase (FAK) inhibition promotes HSPC mobilisation and proliferation, increased decitabine (DAC) incorporation and DNA hypomethylation in bone marrow and peripheral blood mononuclear cells (MNCs) and increased hematopoietic output from haematopoietic stem and progenitor cells (HSPCs) {colony forming unit-cells [CFU-Cs]}) when used in combination with ASTX727. DAC incorporation and global DNA hypomethylation in peripheral blood and bone marrow MNCs will be assayed longitudinally using a mass spectrometry method (AZA-MS) and cell cycle changes in bone marrow MNCs using a flow cytometry method, which were both developed by these investigators. Data from previous studies conducted by these Investigators, has shown that hypomethylating agents (HMA) do not alter the clonal architecture of mutant HSPCs but increase their hematopoietic output by epigenetic means. To demonstrate that adjuvant decitabine promotes HMA induced changes in mutant HSPCs, the investigators will use a method adapted from Rand and Molloy, and improved by this research group, for use in single cells in combination with simultaneous assessment of mutations and gene expression. Given the known impact of FAK inhibition on stromal and immune cells in the tumor microenvironment, the investigators will also assess longitudinal changes in these components using single cell transcriptomics and mass cytometry. Along with clinical efficacy data, the investigators will assess pre- and post-treatment density of mutant clones by sequencing a panel of genes associated with myeloid malignancies. This study's overarching aim is to assess whether defactinib can be safely combined with ASTX727 to improve clinical outcomes in patients with high-risk MDS, low blast AML and CMML. This study will also provide correlative data to support the underlying hypothesis for use of this combination to optimise future HMA therapy. Treatment of participants will occur in three phases: an initial 'prephase' cycle of monotherapy with ASTX727 (decitabine/cedazuridine) day 1 to 5 of a 28 day cycle (Cycle 1); a combination phase of up to 5 28 day cycles of ASTX727 (decitabine/cedazuridine) in combination with defactinib (VS-6063) (Cycles 2 through 6); and a continuation phase of monotherapy with ASTX727 decitabine/cedazuridine in participants continuing to derive benefit. Participants may continue therapy in continuation phase until progressive disease or the development of unacceptable toxicity. Adverse events during the first combination cycle (Cycle 2) will be assessed to determine the maximum tolerated dose (MTD) for combination ASTX727 (decitabine/cedazuridine) with defactinib (VS-6063).

A First-in-human Study of IBI354 in Subjects with Locally Advanced Unresectable or Metastatic Solid Tumors