Ingolstadt

Within the current trial, two novel strategies are tested in a randomized fashion in patients with atrial fibrillation and status post intracranial bleeding. Patients with ICH were usually excluded from the large NOAC trials and were also not representatively included in the large Watchman device trials. On the other hand, registries show that there is a significant proportion of patients with status post ICH that were implanted with a LAA closure device in clinical routine, and also there are those patients treated with NOAC due to their high stroke risk, despite the risk of recurrent ICH. Both therapies, NOAC and LAA closure are effective in preventing stroke in patients with AF at high risk for stroke. Also, for both therapies there is evidence for prevention of bleedings, especially intracranial bleeding events. Patients within the LAA closure group will have the chance after successful closure of the LAA to quit oral anticoagulation medication and therefore reduce their lifetime risk for bleeding and recurrent bleeding. Patients in the NOAC group are provided with an excellent protection against stroke and a significant reduced bleeding risk compared to Vitamin K antagonist therapy. The trial will help to develop data and hopefully guidelines for management of patients with AF and status post intracranial bleedings. It may help to give physicians data to therapy patients post ICH adequately and help to reduce mortality rates in those patients.

The clinical trial is intended to evaluate the efficacy, safety and economic benefit of coronary lithotripsy compared to other additional procedures (cutting or super high pressure balloon angioplasty, ablative procedures) in lesion preparation and interventional treatment of severely calcified coronary stenoses.

This study has broad inclusion criteria and minimal exclusion criteria to ensure the results are representative of the real-world use of these devices. Enrollment caps will be implemented to ensure patients from approved indications are represented. Individuals who are scheduled to receive an implantable Abbott neurostimulation system are eligible for study consideration. The study will enroll up to 2,000 subjects from up to 100 participating centers. Subject enrollment is expected to be completed within 7 years; subjects will be followed for 5 years. The total duration of the study is expected to be 13 years, including enrollment, data collection from all subjects, and study close out.

The scientific aim of the study is to conduct a multicenter, blinded, randomized and actively controlled trial to test the hypothesis that maintenance ECT (mECT) plus clozapine is superior to treatment with clozapine alone in CRS. Prior to the start of mECT (phase II), an acute ECT series (phase I) should have already led to a significant clinical improvement in CRS patients. The superiority of mECT will be proven by a longer time to relapse and secondarily by a lower number of patients with relapse compared to the control group. Secondary objectives are to test the hypotheses that the global level of functioning and quality of life will increase, and that depression, overall symptoms of the schizophrenic syndrome, concomitant catatonic symptoms, stress and self-stigmatization will decrease compared to the control group. It is also expected that cognitive performance will not only not deteriorate, but will improve over the course of the mECT. Once the positive ethics votes have been obtained, the first patients will be included at the individual centers following successful center initiation. In month 12 at the latest, the first patient should leave phase I after 6-9 weeks as a responder and will be randomized in phase II (clozapine versus clozapine plus mECT). At month 30 the last patient (total n = 84) should have been randomized as a responder from phase I and been included in phase II. At month 36 the last planned patient completes phase II of the study with his/her last study visit. Accordingly, he/she is the last patient to start the 12-month follow-up phase. In month 46 investigators will start final data evaluation and analysis. Investigators will complete the primary publication of the study this time point. After 4 years the last patient completes the 12-month follow-up phase. At study end final data evaluation and analysis regarding the primary endpoint of the follow-up phase takes place as well as the completion and submission of the primary publication of the follow-up.

The trial will consist of both a clinical and translational part. During the study, re-assessments (radiologic assessment, blood and QoL) will be conducted for all trial subject of the trial every 3 months. Tumor biopsies will be collected at screening (baseline sample) and in case of relapse of disease if a new tumor sample is obtained. The objective of the re-assessments is detection of relapse either radiologically or within the translational material (blood samples with ctDNA dynamics and tumor - if available from relapses). CT scans of thorax/abdomen and/or MRI scans will be performed every 3 months within the 2 years after randomization. After the first two relapse-free years, intervals should be stretched to 6 months in the third and following years after study start. Structured follow-up for up to 60 months after randomization should be maintained for both arms. Patients in Arm A receive additive study drug intervention (mFOLFOXIRI or mFOLFOX-6) for up to six months (12 cycles) after randomization with additional clinical and safety assessments.