Mainzerhofplatz, Germany

HEM ISMART-D: Trametinib + Dexamethasone + Chemotherapy in Children with Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol with sub-protocols. The overarching objective is that introducing targeted therapy using a biomarker driven approach for treatment stratification may improve the outcome of children with R/R acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) It is characterized by a shared framework that allows for the investigation of multiple IMPs and generate pivotal safety and efficacy evidence within the sub-protocols to establish and define the benefits and risks of new treatments for children with R/R leukemia. Sub-Protocol D within HEM-iSMART, is a phase I/II, multicenter, international, open-label clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of trametinib in combination with dexamethasone, cyclophosphamide and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with actionable alterations in the RAS-RAF-MAPK pathway will be eligible for sub-protocol D including but not limited to KRAS, NRAS, HRAS, FLT3, PTPN11, MAP2K1, MP2K1 hotspot mutations, cCBL; NF1 del.

MED-EL HEARING SOLUTIONS (MEHS): AN OBSERVATIONAL STUDY

Magseed Pro(R)/ Sentimag(R) Gen3

The purpose of this study is to provide prospective evidence that the Magseed Pro® marker /Sentimag® Gen3 system is safe and effective for marking A. suspicious/biopsy-proven positive axillary lymph nodes; and B. soft tissue lesions including cancer and pre-cancerous change in the breast The devices used in this clinical trial are the Magseed Pro® marker and Sentimag® Gen3 system by Endomagnetics Limited. The Endomag Magseed Pro® Marker System is intended to be placed within the target soft tissue prior to planned surgical removal. The marker, when used in conjunction with the Sentimag® Gen 3 System, can be used as a guide for the surgeon to follow in the excision of tissue. The Sentimag® Gen3 Magnetic Localisation System when used with the Magseed family of markers is indicated to assist in localising soft tissue lesions. The study design is a multicentre international prospective, open label, study of Magseed Pro® marker and Sentimag® Gen3 system in patients with breast and/or lymph node pathology with: A. axillary lymph nodes requiring localisation prior to surgical excision (suspicious and/or biopsy proven lymph node or other pathology indicating removal) and/or B. breast lesions requiring localisation Patients will have the Magseed Pro® marker placed to mark A. surgical excision of suspicious/biopsy-proven axillary lymph node as part of a targeted lymph node biopsy procedure AND/OR B. breast lesions in patients undergoing surgical excision of the targeted breast lesion The Magseed Pro® marker will be localised using the Sentimag® Gen3 system and therafter surgically removed with the target tissue. This study will enrol 224 patients; 112 with Magseed Pro® marker placed to mark breast lesions and 112 with Magseed Pro® marker placed to mark nodes. The expected duration of enrolment is approximately 9 months across all sites with each individual subject's participation lasting approximately 1-38 weeks after enrolment.

Prospective, Multicenter Cohort Study on Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease. The course of the disease is characterized by a slow destruction of bile ducts, and progressive cholestasis. Prognosis depends on the development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) has been established as standard therapy for PBC and improves patients' long-term outcome. However, UDCA is not a uniformly effective drug, and the prognosis of PBC patients insufficiently responding to treatment is markedly worse. For patients with suboptimal treatment response to UDCA obeticholic acid (OCA) as newly approved medication (OCALIVA®) is available as second line treatment. Due to the low prevalence and the slowly progressive course of the disease it is very difficult to investigate the prognosis of subgroups of PBC patients or to evaluate the effectivness of therapeutic interventions on clinical outcomes. Therefore, several national or international registries (UK-PBC Consortium or the Global PBC Study Group) were founded to better characterize the clinical course of PBC patients. Since in Germany a registry for PBC does not exist, the German PBC Cohort is being implemented as observational study to collect data on treatment progress and success in clinical routine that reflects real world conditions in Germany as closely as possible. The effectiveness and safety/tolerability of PBC treatment options (UDCA as standard therapy and second-line treatment options like OCALIVA in case of inadequate UDCA treatment response) will be evaluated. In approximatly 40 sites in Germany routine data is collected. There are no specifications for the diagnosis, therapy and monitoring of the PBC patients. The documentation of the routine data is carried out alongside with guideline recommended treatment intervals of the patients. Furthermore, a critical criterion for the German PBC Cohort study is the involvement of a sufficient number of gastroenterology specialized practices and outpatient clinics that have consciously not been selected based on the strict specifications of a clinical trial and which provide routine treatment for PBC patients. In addition, patient access is designed to be open. Data will be collected on patient groups that represent a majority of the PBC patients in Germany, but who are not being investigated in clinical trials.

The RESPOND Outcomes Study

The specific objectives, falling into three main categories, are as follows: 1. Monitor the uptake of newer antiretroviral treatment (ART) drugs and drugs for treatment of co-infections and co-morbidities; 2. To evaluate the safety profiles of the newer individual ART drugs when used in routine clinical practice as part of either first-line or subsequent treatment regimens. 3. Investigate long term outcomes and clinical disease progression overall and in specific sub-groups The Outcomes study is a collaboration between investigators from clinics and cohorts across Europe, Australia and South America with a willingness to share data and to use a common follow-up schedule and assessment. Participating sites have a commitment to continue to follow this large cohort that is heterogeneous in both its demographic profile and in ART prescribing patterns thus resulting in enough power to answer many key clinical questions. The Outcomes study is a study in the RESPOND International Cohort Consortium of Infectious Diseases. RESPOND is an innovative, flexible and dynamic cohort consortium for the study of infectious diseases, including HIV, built as a generic structure for facilitating multi stakeholder involvement. In RESPOND all collected data is part of a common data repository or 'data lake', which is stored in a database located at CHIP, Rigshospitalet, Copenhagen, Denmark. Data collection in RESPOND is modular with a core data collection module onto which additional modules/studies can be added. Pseudonymised patient data can be entered manually via an online secure platform or be electronically transferred from existing local, regional or national data structures to the data lake. In the Outcomes study data will be collected at enrolment and at annual follow-up (FU) visits. For patients living with HIV-1 enrolled and under FU, demographic, laboratory, therapeutic and clinical data on HIV and viral hepatitis will be collected once a year. Clinical event data (except AIDS other than AIDS defining malignancies) will be collected in real-time on RESPOND event forms.

An International, Multicenter, Prospective Registry on Post-traumatic Long Bones Defects

The purpose of this project is to set up an international, multicenter registry of patient presenting with defects in long bones. Up to date, treatment remains challenging with little evidenced-based recommendations. For this purpose, any patient who presents at a study center with a bone defect of the defined expansion of any long bone is eligible for inclusion. Over a 3-year period as many patients as possible are included from the participating sites, at least 600 patients should be included in the registry. Details on any surgical intervention that is used to treat a bone defect will be recorded. Further patient-related and other pre-defined outcome measures will be collected. There is no formal hypothesis to this registry, hence it will help to identify prevalence and underlying etiologies, evaluate treatment strategies, and highlight possible challenges and complications - and will so help to gather clinical evidence to provide better treatment for patients suffering from a long bone defect.

Transfer of FRozen Encapsulated Multidonor Stool Filtrate for Active Ulcerative COlitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with significant morbidity and mortality. Although the precise cause remains unknown, disturbances in the intestinal microbial community and changes in the crosstalk between the microbiota and the mucosal immune system have been linked to its pathogenesis. As current therapies are limited, there is a medical need for new therapies. Faecal microbiota transplantation (FMT) has been proven to be effective in managing relapsing Clostridium difficile infection (CDI) and preliminary results indicated that also the transfer of filtrates of donor stool (FMFT) drives gastrointestinal microbiota changes and eliminate symptoms in CDI patients. FRESCO is a randomized, longitudinal, prospective, three arm, multicentre, double blind study to determine safety and efficacy of repeated FMT or FMFT compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active UC. The primary outcome will be clinical and endoscopic remission at week 12. This proposal aims to examine: (a) the efficacy of FMT / FMFT as a therapy for active UC, (b) the safety of FMT / FMFT in patients with UC and (c) the microbial and inflammable changes that occur after FMT / FMFT, to help understand how and why it works in this group of patients. All analyses will be conducted in both intention-to-treat (primary) and per-protocol (sensitivity analyses) populations, and the differences in remission rates and relapse rates between the groups will be statistically analysed to determine the efficiency of FMT versus FMFT.

Safety and Efficacy of Fibryga in Congenital Fibrinogen Deficiency

There is a need to increase the body of data on treatment effectiveness and safety in the ultra-rare setting of congenital fibrinogen deficiency. Real-world evidence (RWE) derived from non-interventional studies can describe product utilization, demonstrate value, and facilitate benefit-risk assessments; RWE can only be fully assessed once a product is launched and used in a real-life setting. This post-marketing, observational study is designed to collect information concerning safety, efficacy, and outcomes of Fibryga administration in routine clinical use in patients of any age with congenital afibrinogenemia or hypofibrinogenemia. Documentation of the administration of Fibryga in clinical practice for the treatment of both minor and major bleeding events (BEs) will not only enhance the knowledge on the efficacy and safety profile of Fibryga, but will also gather information that cannot be obtained in the same way in controlled clinical studies. These observational data will support the safety and efficacy data generated with Fibryga in good clinical practice (GCP) clinical studies, providing benefit for both physicians and patients.

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.

Diagnosis-related Outcomes in NeurocriTical Care: Prognostic Estimate by Health-care Providers Versus Risk Scores in Intracerebral and Subarachnoid Hemorrhage

The physicians and nurses responsible for the individual patient's care will be given a questionaire. They are asked to estimate the functional and cognitive status as well as quality of life of their patient. The patient with intracerebral hemorrhage and subarachnoid hemorrhage is examined and assessed with respective established and validated prognostic scores and models at the same time points. The actual prognosis is assessed by telephone interview and questionaires at 3 and 6 months, either from the patient or his/her caretaker.