Venusberg, Germany

A Study of Vonicog Alfa (rVWF) in Children With Severe Von Willebrand Disease (vWD)

A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset AD Caused by a Genetic Mutation

This study will recruit participants from the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS), a multicenter international study supported by the National Institutes of Health (Grant Number U01-AG032438; RJ Bateman), Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) sites, DIAN-TU partner sites, DIAN Expanded Registry (DIAN-EXR), and families identified by the sites. As part of the DIAN-TU-002 protocol, participants undergo longitudinal assessments that include clinical assessment, cognitive testing, magnetic resonance imaging (MRI) and amyloid imaging, and analysis of cerebrospinal fluid (CSF). Participants in DIAN are recruited from families that have at least one member who has been identified as having a mutation linked to dominantly inherited Alzheimer's disease (DIAD). The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) genes that are associated with DIAD have very high penetrance (near 100%). This study will enroll individuals who are either known to have a known disease-causing mutation, or who are at risk for such a mutation (the child or sibling of a proband with a known mutation) and unaware of their genetic status. Because the age at onset of cognitive changes is relatively consistent within each family and for each mutation, an age at onset is determined for each affected parent or mutation as part of the DIAN-OBS study protocol. This study will enroll participants who are asymptomatic and are within a specific window of time of expected age at onset for their family and/or mutation. The ability to identify individuals destined to develop Alzheimer's disease (AD) with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies at asymptomatic and very early stages of dementia. Families with known disease-causing mutations are extremely rare and are geographically dispersed throughout the world. These constraints necessitate a specialized study design. Participants in this study will not yet have developed any symptoms of AD; they will be "asymptomatic" carriers of mutations that cause DIAD and would be expected to perform normally on standard cognitive and functional testing. Further, most mutation carriers will have levels of AD-associated amyloid beta (Aβ) and non-Aβ biomarkers that are the same as non-carriers. Imaging and fluid biomarkers will be used to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest and most subtle cognitive changes will be collected. However, the goal of this study is to address whether decreasing plaque prone Aβ peptides in the absence of measurable or mild elevations of Aβ plaques in participants with minimal to no amyloid plaque at baseline can lead to the subsequent prevention of non-Aβ biomarkers of disease progression. Additionally, because many at-risk individuals decide not to know whether they have the disease-associated mutation, some of the at-risk individuals enrolled in this study will not have the disease-causing mutations; they will be "mutation-negative." It is important to enroll these participants to avoid coercion (e.g., potential participants may feel pressured into genetic testing to learn their genetic status to be eligible for the trial). These mutation-negative individuals will be assigned to the placebo group and data will be used to determine normal ranges of outcome. Participants and site study staff will remain blinded as to these individuals' active or placebo group assignment and mutation status. Thus, the study will be blinded for placebo and for mutation status, except for mutation carriers who are aware of their genetic status. There may be exceptional circumstances as required by local regulation or health authorities where enrollment may be restricted to mutation carriers only, but such mandates will be thoroughly documented and agreed upon by the governing regulatory agency and the study sponsor. This study is an adaptive-platform-based study. Several different therapies (each referred to as a study drug arm) may be tested in order to increase the likelihood that an effective treatment will be discovered. The compounds are selected for this trial based on mechanism of action and available data on efficacy and safety profile. In the case of multiple study arms, the study design includes a pooled placebo group (referred to as the mutation positive placebos) shared by all study drug arms. Mutation carriers will be assigned to a study drug arm and subsequently randomized within that arm in an overall 1:1 ratio to active drug: placebo. Mutation-negative participants will all receive placebo treatment. Participants and study staff will not be blinded as to which study drug arm each participant has been assigned; they will be blinded to whether participants have been randomized to receive active drug or placebo. The study has 2 treatment periods: Stage 1 is a blinded placebo-controlled period that will continue until the last randomized participant completes 4 years of treatment (i.e., a common close design), and Stage 2 is an open-label period of 4 years (with a planned 2-year interim efficacy analysis) in which all mutation carriers will receive active drug. At the start of Stage 2, participants who were randomized to placebo in Stage 1 will follow the same dose titration schedule and MRI safety schedule used in Stage 1. Participants who were randomized to active drug in Stage 1 will follow a mock dose titration and will have the same MRI safety schedule used during the initial drug titration as Stage 1 but will remain on the dose that they were on at the end of Stage 1. This will protect the blind to the original treatment assignment from Stage 1. Participants, investigators, and the sponsor's clinical team will remain blinded throughout the study to the Stage 1 treatment assignment. Stage 1 of the study is designed to test whether the study drug can slow, prevent, or reverse progression of Aβ pathology associated with AD and Stage 2 is designed to assess the study drug's effect on non-amyloid biomarkers of AD that may lead to future slowing or prevention of clinical symptoms of dementia. Biomarker, cognitive, and/or clinical endpoints will be specified for each study drug arm. Biomarker data will be analyzed for pre-specified endpoints consistent with the drug's mechanism of action and other AD biomarker outcomes. The clinical and cognitive assessments are designed to assess subtle cognitive changes that may be detectable before the onset of dementia as well as cognitive and clinical decline in symptomatic groups. Roche announced a decision to discontinue most of the company's global trials of gantenerumab. The DIAN-TU has paused the DIAN-TU-002 Primary Prevention Trial related to gantenerumab while considering other potential options for this platform trial. The DIAN-TU plans to re-launch the DIAN-TU-002 Primary Prevention Trial with remternetug in collaboration with Eli Lilly and Company as part of this Master Protocol. The remternetug arm is posted under NCT06647498.

A Trial to See if the Combination of Fianlimab With Cemiplimab Works Better Than Pembrolizumab for Preventing or Delaying Melanoma From Coming Back After it Has Been Removed With Surgery

ABTECT - Maintenance

All eligible subjects who have completed either one of the induction studies above mentioned, will be given the opportunity to take part in the present ABX464-107 study which consists of 2 treatment phases. This study consists of a 44-week maintenance treatment phase (Part 1 and Part 2), followed by a 4-year Long Term Extension (LTE) treatment phase and a 28-days follow-up period consisting in the End of Study (EOS) visit. The maintenance phase is a 44-week double blind, placebo-controlled, phase. Subjects who are clinical responders after 8 weeks induction will be randomized to Part 1, and those who are non-clinical responders will be randomized to Part 2. At the end of the 44-week maintenance phase, subjects will continue their allocated treatment until the maintenance phase is unblinded. Once the study is unblinded, all subjects receiving obefazimod will continue their allocated treatment. Subjects receiving placebo will be allocated to obefazimod 25 mg or can terminate the study.

PLAsma Genomic Testing in Patients With Advanced Non-Small Cell Lung Cancer: The PLAN Study

Background Genomic Testing in Non-Small Cell Lung Cancer Tissue genotyping of therapeutically actionable alterations is a standard diagnostic requirement for patients with advanced non-squamous NSCLC. Tissue genotyping represents a gold standard, with both a sensitivity and specificity for identifying common genomic alterations of >90%. NSCLC represents a genomically diverse cancer. Detection of genomic alterations has progressed over the past decade, now including detection of mutations such as KRAS, EGFR, ERBB2, BRAF, MET and fusions including ALK, ROS1, NTRK and RET genes, as well as co-occurring mutations on tissue samples. The ability to detect these mutations has led to discovery of molecularly defined subsets of NSCLC, and a rapid growth in the development of targeted therapies. Actionable oncogenic driver mutations, which lead to uncontrolled cell growth, are detected in up to 64% of lung adenocarcinomas. The most commonly observed oncogenic driver mutation in NSCLC is KRAS, observed in up to 30% of cases, which has led to the development of agents such as sotorasib and adagrasib to target KRAS G12C mutations after failed first line systemic therapies. The development of EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib, gefitinib or erlotinib, and ALK directed therapy with crizotinib, alectinib and ceritinib has led to significant improvement in survival in patients with NSCLC over the past decade, and shifted the focus to developing improved detection methods of these mutations for first-line targeted therapy. Each actionable mutation detected has led to the rapid expansion of available therapeutic options beyond those mentioned above and changed the landscape of lung cancer treatment. The majority of NSCLC is diagnosed at an advanced stage (stage III or IV), and it is often diagnosed with a core biopsy or cytology specimens. Oncology and pathology societies recommend that molecular testing turnaround times not exceed 10 working days yet up to 30% of these specimens are insufficient to allow for tissue genotyping necessitating repeat biopsy. Patients may thus clinically deteriorate while waiting for genomic test results. In those patients who have insufficient samples on initial biopsy and require repeat intervention, this can prolong the time from diagnosis to treatment by more than 28 days. The methods by which these mutations are detected are continually evolving, including DNA sequencing, DNA allele-specific testing, RNA sequencing, fluorescent in situ hybridization (FISH) to detect fusion genes, and next generation sequencing (NGS). Both DNA and RNA sequencing have been shown to detect actionable mutations, but certain large panels can miss small exon skipping or fusion alterations, and thus a sequential approach may be warranted. In certain mutations, RNA sequencing can detect a higher proportion of MET exon 14 skipping. Frequently a hotspot panel is used to detect a range of commonly occurring mutations, and if negative for these mutations, single gene sequencing can be done for less common mutations, which is time consuming and can further delay treatment. NGS has become the gold-standard method to detect actionable mutations, and was recommended by the European Society for Medical Oncology (ESMO) in 2020 in advanced non-squamous NSCLC, as well as in other malignancies including cholangiocarcinoma, prostate and ovarian cancers. NGS provides a broader test platform, and can assess many more potential gene alterations. The MOSCATO trial assessed the use of high throughput genomic analyses including NGS and showed improved outcomes in advanced cancer. Specifically in NSCLC, NGS has shown significantly improved outcomes, by identifying patients who will derive the greatest benefit from targeted therapies, therefore reducing toxicity related to ineffective therapies with certain mutations. Plasma genotyping in non-small cell lung cancer Plasma genotyping, or 'liquid biopsy,' is a relatively new technology in which circulating tumour DNA (ctDNA), shed into the bloodstream by tumours, is detectable by next generation sequencing. This technology, while associated with a slightly lower sensitivity (80%), has >96% concordance for tissue testing of EGFR, ALK, ROS1 and BRAF mutations. In addition, the median turnaround time is just 7-10 days, without the associated risks and costs of invasive biopsy. Recent studies have shown the dynamic nature of tumour cells including the development of resistance mechanisms in EGFR-mutated tumours. As such, many cancer centres, including some based in Ireland, have used liquid biopsy as a means of surveillance for these resistance mechanisms over time rather than submitting a patient to multiple repeat biopsies. More recently many centres in North America and Europe have utilised liquid biopsy for assessing genomic alterations for targeted therapies in lung cancer upfront at the time of tissue sampling, thereby reducing the time to treatment commencement. This approach is supported by several high-level papers, including the NILE study, a prospective study of 282 patients with advanced untreated NSCLC that showed concordance between tissue and plasma genotyping and a significantly faster turnaround time from 15 to 9 days. A single centre study in the USA showed that concurrent plasma and tissue testing in NSCLC increased the detection of actionable mutations by 15%, and hence increased the number of patients receiving targeted therapies. As well as the oft needed requirement for repeat biopsy due to a lack of tumour tissue for NGS, patients with advanced NSCLC often have a poor ECOG performance status which can limit the possibility of primary invasive procedures or repeat tissue sampling, and in some cases, the location of the tumour site may not be amenable to biopsy. In the event that tissue can be retrieved by invasive procedure, storage of these samples, for example with formalin fixation, can lead to false positive results on next generation sequencing. Invasive sampling is often associated with high cost, due to the number of clinicians, and supportive staff available. Blood sampling is minimally invasive during the initial diagnosis, bypasses the time required to schedule bronchoscopy or radiologically-guided biopsies and allows immediate processing of samples. Although the use of plasma genotyping has expanded in recent years, it is likely that it would remain an additional tool alongside tissue genotyping, as tissue samples can provide morphology and elucidate primary sites of disease. Rationale We propose this study to evaluate the feasibility of a plasma-based circulating tumour DNA mutation testing pathway using NGS and initiated at the Rapid Access Lung Cancer Clinic (RALCC) for patients with suspected NSCLC in Ireland. This proof of principle initiative aims to establish a robust patient pathway for systematic somatic mutation testing in patients with NSCLC in Ireland using plasma-based testing. Plasma will be tested for circulating tumour DNA mutations using a validated NGS-based assay, at one of two testing laboratories in Ireland. Proving feasibility through a clinical trial in Ireland is crucial to inform successful applications for authorisation of liquid biopsy to the National Clinical Cancer Programme and to inform clinical trials that aim to identify novel therapies for Irish patients. We believe an upfront plasma-based pathway would lower median turnaround time in the Irish context. Liquid biopsy testing of patients in the RALCC for tumour mutations should ensure that more patients have access to precision medical therapies. Moreover, this approach is likely to significantly improve the identification rate of patients with NSCLC actionable genomic alterations, with resultant benefits for these patients in terms of cancer treatment. This study will also report on the currently unknown frequency, characteristics, disease course, and treatment patterns of somatic mutations in an Irish population with NSCLC. Hypothesis Upfront plasma-based tumour genotyping of patients with advanced NSCLC with the goal of guiding treatment selection is feasible to implement and will reduce the time to treatment compared with tissue genotyping. Planned Analysis This proof of principle initiative aims to establish a robust patient pathway for systematic somatic mutation testing in patients with NSCLC in Ireland using plasma-based testing. Plasma will be tested for circulating tumour DNA mutations using a validated NGS-based assay, at one of two testing laboratories in Ireland. The Cancer Molecular Diagnostics (CMD) laboratory at St James's Hospital will perform the tumour test on using an in- house Roche AVENIO ctDNA Expanded panel (Basel, Switzerland). The Histopathology Department at Beaumont Hospital will use an in-house Roche AVENIO ctDNA Expanded panel on the Illumina MiSeq NGS platform (California, USA). Both assays will be validated on a training tumour set. In parallel to ctDNA testing, tumour biopsy tissue testing will be carried out as per standard of care. Liquid biopsy results will be reviewed by the treating clinician for treatment decision purposes however the treatment decision will remain at the discretion of the treating medical oncologist. It is recognised that liquid and tissue biopsy both have an excellent specificity (>95%). However, liquid biopsy may have a lower sensitivity in the region of 80%. As such, there may be genomic alterations identified on tissue biopsy not identified on liquid biopsy and less likely - vice-versa. In that event, the genotyping which has reported a genomic alteration will be considered the most clinically relevant results as the likelihood of a false positive result is very low (< 5%). However, final treatment decision will remain at the discretion at the treating medical oncologist.

Automated Diagnostic Performance of Smartwatch ECG for Arrhythmia Detection Using the PulseAI Neural Network.

Under subject consent, subjects will have a 12-lead ECG immediately followed by a smartwatch ECG. The heart rhythm and ECG interval measurements will be compared between the 12-lead ECG and smartwatch ECG. The arrhythmias will include: - Atrial Fibrillation/Flutter - Tachycardia - Bradycardia - Premature Atrial Contractions - Premature Ventricular Contractions

A Study to Assess Effectiveness and Safety of Deucravacitinib Compared With Placebo in Participants With Active Systemic Lupus Erythematosus (SLE)

Safety, Tolerability, Pharmacodynamic, Efficacy, and Pharmacokinetic Study of DYNE-251 in Participants with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping