Grã¼nhainichen, Germany

A Study of Zasocitinib in Adults With Psoriatic Arthritis Who Have Not Taken Biologic Medicines

A Study on the Safety of an Investigational Chickenpox Vaccine, When Given to Healthy Children, 12 to 15 Months of Age

Bispecific T-cell Redirectors as Part of First Line Treatment in Transplant Eligible Multiple Myeloma Patients

A total of 50 transplant-eligible patients with newly diagnosed multiple myeloma in need of treatment will be enrolled. The study consists of three phases: Induction, Consolidation, and Follow-up. Induction will consist of Dara-VRd and consolidation Part I will include talquetamab and Part II will include teclistamab. Follow-up Phase After consolidation, treatment continues upon physician's choice: the options are ASCT with maintenance or only maintenance with lenalidomide. Efficacy will be evaluated by serum/urine electrophoresis monthly; by serum/urine immunofixation, bone marrow morphology and flow cytometry when CR/sCR is suspected; MRD will be evaluated by NGS ( at the level of 10-6) and FDG PET-CT ( by Deauville score) at various timepoints during induction, consolidation and follow-up. Participants quality of life, symptoms, functional and general well-being will be captured using 3 PRO measures ( PRO-CTCAE, EORTC QLQ-C30, FACT-Cog). The safety of study drugs will be assessed by physical examinations, vital signs, ECGs, clinical laboratory tests, neurologic examinations (including ICE scores), ECOG performance status, and AE monitoring according to NCI-CTCAE Version 5.0), grading of CRS and ICANS will be assessed based on ASTCT guidelines.

A Study in Patients With Moderate to Severe Plaque Psoriasis to Evaluate the Efficacy and Safety of ESK-001

Nordic ORgan Preservation Pilot Approach Nonrandomised Single-Arm Trial for Non-Operative Management of Rectal Cancer

Background: Non-operative management (NOM) for rectal cancer is an accepted treatment option that has not been commonly utilized in Finland but has been widely adopted in major cancer centers worldwide. NOM can be considered if the rectal tumor disappears with neoadjuvant treatment, resulting in a complete clinical response. Objective: The aim of the study is to establish a unified NOM protocol for national use and determine whether the outcomes of Finnish and Estonian treatment practices align with international experiences. Design: The study is a prospective, non-randomized, single-arm, international multicenter trial examining the oncological and quality-of-life consequences of NOM. Primary Endpoint: The primary endpoint is disease-free survival 2 years after the initiation of NOM. Secondary Endpoints: These include overall survival, disease-specific survival, survival free from total mesorectal excision (TME) surgery, survival free from circulating tumor DNA (ctDNA) detection after complete clinical response, recurrence-free survival, incidence of local recurrence and metastases, salvage TME success rate, quality of life at 1 year post-NOM, and treatment-related morbidity up to 5 years. Inclusion Criteria: Patients must have histopathologically confirmed primary rectal adenocarcinoma before neoadjuvant treatment, achieve clinical complete response (cCR) after neoadjuvant therapy, and express willingness to undergo rectum-preserving treatment after considering the risk of recurrence. Exclusion Criteria: Patients with evidence of metastasis at diagnosis, aged under 18, those not receiving neoadjuvant treatment, or those unable to provide informed consent are excluded. Diagnosis and Treatment: Pretreatment of patients follows standard practice. Upon meeting inclusion criteria with confirmed cCR, patients undergo protocolized monitoring with clinical examination, laboratory tests, and imaging. Randomization: No randomization is performed. Follow-up: Patients are monitored every 3 months for the first 2 years, then every 6 months for 3 years. Monitoring replaces surgical intervention unless cancer recurs. Follow-up is part of standard care, with costs covered by the healthcare system. Safety: Incidence of local recurrence and success of resection post-recurrence are monitored closely. If over 30% local recurrence occurs post-cCR, it may necessitate study termination at the center. Data Collection: Clinical data are entered into electronic case report forms (eCRFs) based on primary healthcare documentation and stored pseudonymized on the primary research center's server. Molecular and pseudonymized clinical data are collected securely for analysis. Sample Size Calculation and Statistical Analysis: A sample of 200 patients is estimated to provide sufficient data for the primary and key secondary endpoints and to meet other study objectives accurately. Data Handling: Data handling adheres to privacy legislation, with information stored pseudonymously.

A Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Multiple Sclerosis.

Participants with relapsing MS from the Phase 2b LTS16004 parent study will continue open-label (OL) tolebrutinib. All participants from the Phase 3 parent studies (EFC16033, EFC16034, EFC16645, and EFC16035) will learn which treatment they received in the parent study: - If from one of the Phase 3 relapsing MS studies and on teriflunomide, an accelerated elimination procedure or a 3-month washout period is required prior to starting OL tolebrutinib. If on teriflunomide, and benefiting and recommended by the Investigator, the participant may opt to continue teriflunomide outside of the LTS17043 study, if clinically appropriate. If on tolebrutinib, the participant will continue tolebrutinib. - All participants from one of the Phase 3 progressive MS studies will start OL tolebrutinib. - If a participant already started OL tolebrutinib in the Phase 3 parent study this will be continued. - RMS participants who are not eligible for OL tolebrutinib per Health Authority and/or ethics committee decisions on the study conduct (ie, partial hold on initiation of tolebrutinib) will continue their parent study treatment assignment as per their randomization from the parent study. The treatment duration per participant will be approximately 3 years of OL tolebrutinib.

Study of Perioperative Dostarlimab in Participants With Untreated T4N0 or Stage III dMMR/MSI-H Resectable Colon Cancer

A Clinical Study That Will Measure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anxiety Disorder

This is a multicenter, randomized, double-blind, parallel-group, flexible dose, outpatient study evaluating the efficacy and safety of SEP-363856 flexibly dosed (50 - 75 mg/day) versus placebo over an 8-week Treatment Period in subjects with GAD. This study is projected to randomize approximately 434 subjects to 2 treatment groups (SEP-363856 [50 - 75 mg/day] or placebo) in a 1:1 ratio. Approximately 30 additional subjects (N = 15 per treatment group) are projected to enroll in the Japan Cohort. Treatment assignment will be stratified by country. Study drug will be taken at approximately the same time each evening at bedtime .

A Treatment Study Protocol for Participants 0-45 Years With Acute Lymphoblastic Leukaemia

ALLTogether is a European clinical treatment study for acute lymphoblastic leukaemia (ALL) in infants, children and young adults. The aims are to improve survival and quality of survival. In young people, ALL has excellent outcome with an overall survival of about 92% in children and 75% in young adults. Infants with BCP-ALL and KMT2A-rearrangements have a worse outcome and are treated according to separate protocols, but infants with KMT2A-germline and T-cell ALL have acceptable outcome on standard ALL therapy. However, patients still die of disease - from relapse because of under-treatment and a large fraction of patients are also over-treated: All patients risk treatment-related death and some suffer long-term side-effects or secondary cancer. To show improvement with such good survival, large populations are needed. Study groups from Sweden, Norway, Iceland, Denmark, Finland, Estonia and Lithuania (NOPHO), the UK (UKALL), the Netherlands (DCOG), Germany (COALL), Belgium (BSPHO), Portugal (SHOP), Ireland (PHOAI), and France (SFCE), have designed a common treatment protocol. The study has a complex clinical trial design with sub-protocols (the randomisations / intervention) connected to a master protocol. The master protocol consists of well established therapy-elements and in its design typical for current ALL therapy. The master protocol therapy is in the study design considered as standard of care (SOC) therapy for infants, children and young adults with ALL. The study structure is defined by a master protocol onto which randomised and interventional sub-protocols as well as sub-studies may be added, run and stop in a modular fashion. The randomisations / intervention may identify therapy that is less toxic, but equally efficacious for sub-groups of patients and innovative therapy that may reduce relapses and death from ALL. In the master protocol, improved risk-stratification is likely to increase survival and reduce unnecessary toxicity and the introduction of therapeutic drug monitoring (TDM) of Asparaginase activity will make the use of Asparaginase more rational and efficient and may thus improve overall outcomes. The investigators hypothesise that patients stratified to the standard-risk group are over-treated. Therefore, it will be tested if the treatment can be safely reduced. In the R1 randomisation, patients will be randomised to receiving the Delayed Intensification (DI) phase of therapy with or without the anthracycline Doxorubicin. A similar hypothesis of over-treatment will also be tested in patients stratified to the intermediate risk-low group. In the R2 randomisation patients will be randomly assigned to either removal of Doxorubicin during the DI phase or removal of Vincristine and Dexamethasone pulses during the maintenance phase or to the control group, which will be treated with Doxorubicin in DI as well as Vincristine and Dexamethasone pulses during maintenance. Patients will only be randomised once. Randomisation R1 and R2 are only considered for children since adults have worse outcome and very poor survival after relapse, but the risk-stratification is likely to reduce the number of high-risk cases also in the adult-group. Patients stratified as intermediate risk-high (IR-high) are identified as having an increased risk of relapse and thus a less favourable prognosis than the standard- and intermediate risk-low groups, but a more favourable prognosis than the high risk patients. The majority of all relapses in childhood ALL is expected to occur in the IR-high group. Following a relapse, only approximately 40% of the children can be successfully treated again and for adults the corresponding figure is less than 20 %, so preventing relapses is very important. New treatment options that improves the antileukaemic efficacy and which have an improved safety profile are urgently needed. For IR-high patients Randomisation 3 (R3) is available. In R3 patients will be randomised to receive either: 1. the addition of two cycles of Inotuzumab ozogamicin (InO) - Besponsa®, before start of the maintenance phase. After these cycles, the patients randomised to the InO arm will receive maintenance for the same duration as in the control arm. 2. the addition of low dose 6-tioguanine (6TG) as an addition to the standard maintenance therapy. 3. standard maintenance therapy Patients with ABL-class fusions in their leukaemic clone will, as a non-randomised experimental intervention, be treated with an addition of a tyrosine-kinase inhibitor during the induction phase (for patients <25 years) and from the consolidation phase (patients ≥25 years). This intervention may shift therapy for previously resistant cases to lower intensity treatment with the associated reduced morbidity and may also reduce the number of relapses in analogy with the results in Ph+ ALL. The reason for not performing a randomised comparison is the rarity of the aberration and also the diversity of ABL-class fusions, reducing statistical power for any comparison further. For this reason, the results of this intervention may be pooled with other study-groups trying similar approaches. A new intervention is introduced for Down syndrome patients with CD19 positive ALL: ALLTogether1 DS (NRI2). For Down syndrome-ALL patients who have end of Induction MRD detectable but <25% two conventional chemotherapy consolidation blocks will be replaced with two blocks of Blinatumomab. For high-risk B-lineage patients, CAR-T therapy can be an alternative to high-risk blocks and stem-cell transplant, but in this case the intervention (CAR-T infusion) will be performed outside the ALLTogether1 study. However, the stratification-system in ALLTogether1 will define the population with a potential CAR-T indication. ALLTogether1 also includes five sub-studies: Efficacy and pharmacokinetics of Imatinib in ABL-class fusion positive ALL Target population: All ABL-class patients enrolled in the ALLTogether study. Biomaterials to be collected at diagnosis, during TKI treatment, follow-up and relapse. Aims 1. To determine the efficacy and dosing target of imatinib in the treatment of ABL-class leukemia 2. To find the best discriminative biomarkers for TKI response in ABL-class ALL 3. To determine the frequency of intrinsic (at diagnosis) and acquired TKI resistance (due to treatment), including backtracking of mutations using imatinib PK/PD findings during treatment 4. To find causes of TKI resistance in ABL-class patients 5. To describe the pharmacokinetics of Imatinib in TKI-treated patients Objectives 1. To determine the percent of ABL-class patients who need to switch from IR-high to HR because of high MRD levels 2. To determine the effect of imatinib exposure on clinical outcome, including pharmacokinetic measurements of imatinib 3. To determine the molecular response to imatinib by monitoring fusion gene levels and mutational spectrum at diagnosis and during follow up 4. To determine whether the molecular response parameters reflect the Ig/TCR MRD or flow-MRD response or are a better predictor of therapy failure than Ig/TCR or flow-based MRD monitoring 5. To determine the phosphorylation status of ABL-class proteins and presence of TKI-resistance associated mutations in ABL genes prior to imatinib treatment and the emergence of such mutations during treatment with imatinib 6. To determine the presence of mutations in regulatory /other genes before and during imatinib treatment and functionally address the importance of these mutations in TKI resistance 7. To determine whether the efficacy of TKIs depends on the type of fusion gene 8. To describe inter- and intraindividual variations in imatinib PK (=trough levels) during therapy of ABL-class ALL 9. To describe associations between PK of imatinib and end-of-induction MRD (<25 yrs only) and end-of-consolidation MRD (all patients) 10. To describe associations between imatinib PK and relapse rates (overall, bone-marrow and CNS), event-free survival as well as overall survival; 11. To describe associations between imatinib PK and toxicities (including e.g. height z-scores at diagnosis and end of therapy, pancreatitis, treatment delays) with focus on those toxicities that are routinely monitored in ALLTogether. Biomarkers to Reform Approaches to therapy-Induced Neurotoxicity (BRAIN) Target population: All patients registered on ALLTogether1 aged ≥ 4 years at end of therapy (Arm A) and all patients registered on ALLTogether1 aged 4-21 years at start of therapy (Arm B) and without: 1. Pre-existing neurodevelopmental delay (e.g Trisomy 21) prior to diagnosis of ALL 2. Significant visual or motor impairment preventing use of a touch screen ipad All centres are invited to enrol to arm A (Main BRAIN) of the study. Arm B (Longitudinal BRAIN) will be carried out in selected centres. Aims 1. To implement universal screening of all children for adverse neurocognitive outcomes at the end of treatment using a validated user-friendly computer software programme (CogState) and compare neurocognitive outcomes by treatment allocation (Arm A). 2. To identify risk factors for adverse outcomes including whether acute neurotoxic events are associated with poor performance on cognitive tests at end of therapy compared to patients without acute neurotoxicity (Arm A). 3. To examine changes in neurocognitive performance over time and the risk/protective factors associated with differences in outcome, such as demographic, clinical, and physical/psychosocial factors (Arm B). Primary end-point a. Proportion of children with a z-score <1.5 on detection and/or identification CogState tasks in each treatment arm at the end of ALL therapy. A z-score < 1.5 correlates with moderate cognitive impairment at a level that may require additional support. Secondary and exploratory end-points 1. Association between CogState scores at end of treatment and overt neurotoxic episodes as recorded on the trial adverse event database. 2. Association between Cogstate scores and clinical and demographic variables - age, sex, ethnicity, CNS status. 3. Proportion of children with scores <1.5SD for one card learning (learning), one back (working memory) and Groton's maze (executive function) on different treatment arms. 4. Association between CogState scores and patient reported outcome measures/Quality of life measurements collected as part of the main ALLTogether1 trial. 5. Changes in neurocognitive scores over time, including CogState and BRIEF-2/BRIEF-A scores. 6. Association between neurocognitive scores over time and interactions with demographic variables (age, sex), clinical variables (treatment arm, neurotoxicity), social-emotional and physical functioning (SDQ, PedsQL 4.0 Generic; PedsQL 3.0 Fatigue), and family factors (MEES; PedsQL FIM) Association between asparaginase activity levels and outcome Target population: All patients included in the ALLTogether1 protocol are eligible for participation. Primary aim To study the association between asparaginase activity levels and outcome (MRD, relapse, survival) Secondary aims 1. To evaluate the association between asparaginase activity levels and toxicities, such as pancreatitis, infections and deep venous thrombosis (DVT) 2. To evaluate the association between asparaginase activity levels and hepatotoxicity in a subset of patients CSF-Flow Target population: All patients included in the ALLTogether1 protocol are eligible for participation Aims 1. To use cerebrospinal fluid (CSF) flow cytometry (FCM) to improve the accuracy of diagnostic tests for CNS leukaemia compared to conventional CSF cytology. An associated objective will be to develop a recommended protocol for CSF flow cytometry with external quality assessment to ensure uniformity of measurement across the ALLTogether consortium. 2. To investigate whether negative FCM identifies a group of children at very low risk of CNS relapse, suitable for testing de-escalation of CNS-directed therapy in future trials. 3. To investigate whether positive FCM can identify children at increased risk of CNS relapse and whether patients with persistent positivity (FCM positive at day 15 onwards) might benefit from studies testing escalated CNS-directed therapy or a switch to more intensive treatment arms. 4. To collect matching CSF supernatant for studies comparing CSF FCM with soluble biomarkers (e.g. metabolic, cell-free DNA, proteomic and microRNA). Maintenance therapy pharmacokinetics/-dynamics study Target population: All patients included in the ALLTogether1 protocol are eligible for participation. For IR-high patients participating in the randomised InO- and TEAM sub-protocols, the monitoring of 6-mercaptopurine (6MP)/Methotrexate (MTX) metabolites at three months intervals is mandatory. Aims and specific objectives 1. To map pharmacokinetics of 6MP and MTX during maintenance therapy in all patients in the ALLTogether protocol. 2. To associate metabolite profiles with TPMT and NUDT15 variants, as routinely analysed in ALLTogether. 3. To explore the association of event-free survival with DNA-TG and other 6MP/MTX metabolites. 4. To explore the association between risk of second cancers with DNA-TG and other 6MP/MTX metabolites. 5. To explore the association of risk of invasive infections with DNA-TG and other 6MP/MTX metabolites. 6. To explore the association of risk of osteonecrosis with DNA-TG and other 6MP/MTX metabolites. 7. To explore the association of sinusoidal obstruction syndrome with DNA-TG and other 6MP/MTX metabolites.

Blood Pressure Control in ESH Excellence Centres

The most important task of the European Society of Hypertension is to improve blood pressure treatment and increase blood pressure control, thus decreasing cardiovascular risk, premature cardiovascular and renal morbidity and mortality, with in addition a reduction of health-care costs. More than a decade ago, the European Society of Hypertension established a network of Excellence Centres. Those centres are leading institutions for the diagnosis and treatment of hypertension and thus are front runners of good clinical practice in hypertension management in their countries. An important task of the Excellence Centres is also to be active in research, particularly in projects conducted by the European Society of Hypertension. The ongoing BP-CON-ESH project on the rate of blood pressure control in hypertensive patients addresses the most elementary,but at the same timethe most important aspect in hypertension management, because the observed low rates of blood pressure control is the reason why hypertension is still today the leading cause of death worldwide. In the BP-CON-ESH study we are going to include and analyze treated hypertensive patients seen consecutively by the ESH Excellence Centres. Blood pressure will be measured as usually done in the office, but care will be adopted to make measurements highly standardized in all Centres. The primary goals will be to determine the global, regional and country rates of hypertension control in Europe. Other goals will be to identify global and regional factors associated with blood pressure control in different European regions. It is well known that the overall control of hypertension in Europe is still insufficient. However, the problem is not the same across Europe. Differences in healthcare systems exist among European countries, and in some countries government healthcare system only partially reimburse costs of antihypertensive therapy. There are also differences in gross national product, educational levels, salt consumption, prevalence of obesity and other aspects. These could cause dissimilarities in hypertension prevalence, achieved blood pressure control and cardiovascular mortality among European regions. The results obtained in the BP-CON-ESH project will be used to refine treatment strategies for improvement of blood pressure control and will serve as a basis for assessing future changes and trends in Europe.