Kacyiru, Rwanda

Adjusted High-dose Chemotherapy with Autologous Stem Cell Transplant Vs. Conventional Immunochemotherapy in Elderly PCNSL Patients

Primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is a rare lymphoma affecting only the central nervous system compartment. PCNSL patients are typically 60 years or older and have poor prognoses. However, there are alternative treatment approaches to consider with the potential to improve medical outcomes for this patient population. The current standard of care in Germany and many international centres for patients 65 and older is treatment with R-MP, comprising rituximab, high-dose methotrexate (HD-MTX) and procarbazine followed by maintenance therapy with procarbazine. An alternative approach comprised of a shorter induction treatment with rituximab, HD-MTX and cytarabine (MARTA) followed by age-adjusted high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) was recently shown to be feasible and effective in elderly PCNSL patients considered eligible for high-dose chemotherapy requiring autologous stem cell transplantation. Nevertheless, data evaluating this short duration treatment approach remains scarce, and randomized trials have not yet been published. The objective of the PRIMA-CNS trial is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with R-MP followed by maintenance with procarbazine in elderly patients with newly diagnosed PCNSL; not only regarding survival and remission after treatment but also regarding standards like quality of life (QOL) and treatment related morbidities. Results of this randomized trial will either change the standard of care to an intense and shorter treatment approach or re-define R-MP as a proven treatment standard. In addition, a geriatric assessement is implemented in this trial with the goal to better define transplant eligibility. If this trial shows the superiority of HCT-ASCT, the investigators will establish an improved treatment standard with increased chances for long-term remission and cure and reduced frequency and length of chemotherapy treatment. Considering the poor prognosis of this patient population, this randomized phase III trial is of great clinical importance to provide patients, the patients' families and care takers with optimal treatment.

Remote Support for Cochlear Implant Recipients: Evaluation of the HearCare MED-EL App

Remote care solutions can provide cochlear implant users a greater convenience, accessibility, and personalized care. These advantages stem from the ability to fine-tune and adjust their devices from the comfort of their own environments, without the need for frequent and time-consuming in-person clinic visits. Remote care allows clinicians to remotely assess data, provide guidance, and make necessary adjustments, all while minimizing the need for physical presence. This streamlined approach translates to increased capacity for serving a larger number of patients, ultimately leading to improved patient outcomes. The HearCare MED-EL App is a mobile smartphone application designed for recipients of at least one compatible MED-EL cochlear implant and respective audio processor. The app manages technical checks on compatible cochlear implants and audio processors, creates and utilizes backups of audio processor configurations, and performs updates of audio processor configurations by acting as an executive organ of the MAESTRO System Software. The app reduces face-to-face follow-up appointments of users/caregivers with hearing professionals while maintaining safe and ongoing care for all individuals. This clinical investigation aims to evaluate the HearCare MED-EL App regarding safety and performance.

PROtective Ventilation With FLOW-Controlled Ventilation

The optimization of intraoperative ventilation is important in patients under general anesthesia, when physiologic breathing is replaced by non- physiologic artificial ventilation. Especially in patients undergoing robot- assisted laparoscopic surgery, intraoperative ventilation can be challenging, because of changes in compliance of the respiratory system and associated problems in gas exchange, due to the pneumoperitoneum and often extreme body positioning. Intraoperative lung-protection strategies have steadily improved in recent years to reduce complications from mechanical ventilation, but postoperative pulmonary complications remain a risk factor for increased morbidity and mortality. This pilot trial will be conducted to evaluate the safety and feasibility of intraoperative FCV during robot-assisted laparoscopic abdominal, urologic, or gynecologic surgery, and will inform the design of a future trial that will test the efficacy of intraoperative FCV compared to PCV in these patients. In an international multicenter randomized clinical pilot trial, intraoperative flow-controlled ventilation (FCV) will be compared with pressure-controlled ventilation (PCV) in patients scheduled for robot-assisted laparoscopic abdominal, urologic, or gynecologic surgery. This pilot trial is designed to test the safety and feasibility of FCV, and to inform the design of a future trial testing the efficacy of FCV with regard to postoperative outcomes, including postoperative pulmonary complications. The ventilation modes are conducted with CE-marked medical devices (anesthesia ventilators or medical ventilators), however these medical devices themselves are not under investigation. All CE-marked standard medical devices from varied manufacturers in use at the participating study centers will be used in full accordance with the instructions for use. Given that ventilation strategies inherently carry certain risks, yet remain essential in the context of general anesthesia and surgery, it is ethically justified to first conduct a pilot trial. The potential benefits of FCV are significant and warrant investigation. Therefore, the investigators find it appropriate to compare FCV with existing strategies such as PCV, as the investigators anticipate meaningful improvements in patient outcomes with minimal additional risk. The investigators hypothesize, that FCV is a safe and feasible ventilation strategy in patients undergoing robot-assisted laparoscopic surgery. The primary objective of this study is to evaluate the safety of intraoperative FCV in patients undergoing robot-assisted laparoscopic surgery, with a focus on: gas exchange, including both oxygenation and decarboxylation; minute ventilation, during all phases of intraoperative ventilation; key ventilator settings and ventilation parameters; respiratory complications, including pneumothorax and hemodynamic complications, including hypotension and arrhythmias. The secondary objectives are to assess the feasibility of intraoperative FCV and the study protocol in patients undergoing robot-assisted laparoscopic surgery, including an evaluation of the use of FCV. The need for rescue ventilation strategies, i.e., whether FCV (as well as PCV) can be used during all phases of intraoperative ventilation; and compliance with the study protocol, omissions in the eCRF, and the feasibility of follow-up, i.e., how well each PPC can be captured. The explorative secondary objective concerns the primary endpoint of a future randomized clinical trial testing the efficacy of FCV, i.e., its effects on postoperative pulmonary complications. Herein the investigators will determine the exact incidence, and define the effect size of the intervention. The primary endpoint of this pilot trial is a set of safety parameters for FCV, including: gas exchange: (hourly) PaO2, PaCO2, SpO2 and end-tidal CO2; minute ventilation: (hourly) total minute volume; ventilator settings and ventilation parameters: (hourly) tidal volume, respiratory rate, PEEP and PIP, FiO2, driving pressure and mechanical power of ventilation, and respiratory system compliance and elastance; intraoperative respiratory complications: (any time point) pneumothorax. intraoperative hemodynamic complications: (any time point) occurrence of hypotension, defined as a mean arterial pressure (MAP) below 65 mm Hg, lasting longer than 1 minute (not related to the surgical course or anesthetic interventions, according to the attending anesthesiologist); and (hourly) vasopressor support and dose; and (any time point) occurrence of arrhythmias, and intervention for arrhythmias. Secondary endpoints focus on evaluating the feasibility of intraoperative FCV and the study protocol, including: ventilation protocol adherence; and study protocol adherence; and completeness of the eCRF and follow-up of PPCs. The explorative secondary endpoint will compare FCV with PCV ventilation with respect to predefined and previously used postoperative (pulmonary) complications in the first seven postoperative days, including: mild respiratory failure, defined as the occurrence of one or multiple of the following conditions after more than two days postoperatively: the occurrence of oxygen saturation (SpO2) < 90% or partial pressure of oxygen in the arterial blood (PaO2) < 7.9 kPa (or < 50 mm Hg) on room air, but responding to supplemental oxygen; or a sudden increase in supplemental oxygen requirement to maintain adequate saturation (SpO2 > 90%) in patients receiving routine postoperative oxygen therapy; or any level of supplemental oxygen; severe respiratory failure, defined as need for noninvasive or invasive mechanical ventilation, or a PaO2 < 60 mm Hg (or < 7.9 kPa) or SpO2 <90% despite supplemental oxygen in spontaneously breathing patients; dyspnea, defined as the patient's perception of an uncomfortable abnormal awareness of breathing or respiratory limitation (shortness of breath, inability to take a deep breath, or chest tightness); productive cough, defined as cough that produces sputum or mucus; bronchospasm, defined as newly detected expiratory wheezing treated with bronchodilators; suspected pulmonary infection, defined as receiving antibiotics and meeting at least one of the following criteria: new or changed sputum, new or changed lung opacities on chest radiograph when clinically indicated, tympanic temperature > 38.3°C, white blood cell count > 12,000/μL; pulmonary infiltrate, defined as any unilateral or bilateral infiltrates on chest radiography; aspiration pneumonitis, defined as respiratory failure after the inhalation of regurgitated gastric contents; atelectasis, defined as lung opacification with shift of the mediastinum, hilum, or hemidiaphragm towards the affected area, and compensatory overinflation in the adjacent non-atelectatic lung on chest radiography; ARDS (according to the new global definition of ARDS); pleural effusion, defined as blunting of the costophrenic angle, loss of the sharp silhouette of the ipsilateral hemidiaphragm in upright position, evidence of displacement of adjacent anatomical structures or (in supine position) a hazy opacity in one hemithorax with preserved vascular shadows on chest radiography; pneumothorax, defined as air in the pleural space with no vascular bed surrounding the visceral pleura on chest radiography; cardiopulmonary edema, defined as clinical signs of congestion, including dyspnea, edema, rales and jugular venous distention, with the chest radiograph demonstrating increase in vascular markings and diffuse alveolar interstitial infiltrates; and death in hospital (defined as death from any cause during hospitalization) The patient population will be selected by the following criteria: Inclusion criteria: aged ≥ 18 years; and scheduled for elective robot-assisted laparoscopic abdominal, urologic or gynecologic surgery in supine or Trendelenburg position; AND with an increased risk of PPC, according to the ARISCAT risk score (≥ 26 points); OR the combination of age > 40 years, scheduled surgery lasting > 2 hours and planned to receive an intra-arterial catheter for blood pressure monitoring during the surgery; and able to give written informed consent. Exclusion criteria: body weight < 40 kg; ASA Physical Status Classification System score IV - VI; previous enrolment in the current study; being the study investigator of this study, his/her family members, employees and other dependent persons; known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating; or no written informed consent. The sample size calculation is based on the following assumption: To estimate the appropriate sample size for this pilot trial, the investigators considered both safety and feasibility across multiple centers. Assuming a target of 10 to 15 participants per randomization group in each of the four centers, the total sample size would range from 80 to 120 participants (4 centers × 10-15 participants × 2 randomization groups). For practical purposes and to ensure a robust assessment of the trial's objectives, the investigators have selected a total sample size of 100 participants. This number balances logistical feasibility with the need for adequate data to assess safety outcomes. The statistical analysis will be performed accordingly. Balance between study groups will be ensured by randomization and an appropriate sample size. Baseline characteristics will be assessed by appropriate tests to demonstrate balance between groups. The investigators will primarily perform an intention to treat analysis, and will add a per protocol analysis as sensitivity analysis. Tests for normal distribution of the data will include QQ-plot assessments. Potential differences between the two groups in the distribution of dichotomous data are analyzed by chi-square statistics. Continuous data are analyzed by parametric (t-test, ANOVA) or non-parametric (Mann-Whitney U) test for unpaired comparison as appropriate. A sub-analysis related to sex, age, type of surgery will be performed for all study endpoints. Datasets to be analyzed, analysis populations All participants will be analyzed in terms of the respective endpoint parameters. The data of patients who leave the study prematurely are analyzed independently of the completion of the study (intention to treat). A subgroup analysis with respect to sex, age, type of surgery will be performed for all study endpoints.

Revumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML

A Study to Evaluate ALN-HTT02 in Adult Patients With Huntington's Disease

Neurofilament Light Chain in Amyotrophic Lateral Sclerosis

The aim of this study is to investigate the correlation between the NfL serum concentration and the natural course of the disease, the ALS progression rate as measured by the ALS functional rating scale (ALSFRS-R), and specific phenotypes of ALS. The results of the study will contribute to the assessment of disease progression and the prognosis making of ALS. Furthermore, the performance of NfL as a therapeutic marker of ALS medicines and non-pharmacologic treatment options will be investigated. A systematic analysis of the NfL serum concentration in an extended cohort of ALS patients using the Single Molecule Analysis method (SIMOA) will be performed. Research objectives comprise: - Correlation of NfL with disease progression, including duration of ALS disease - Correlation of NfL with the course of ALS (classic ALS or variants in the motor neuron involvement or the regional propagation patterns) - Correlation of NfL with the progression rate of ALS Cohorts on phenotypic variants: The clinical phenotype of ALS will be differentiated according to the motor neuron involvement or regional propagation patterns of disease onset and clinical course. ALS variants in relation to motor neuron involvement: - Typical ALS: clinical features for an affection of the 1st and 2nd motor neurons are present - Progressive muscular atrophy (PMA): only clinical features for an affection of the 2nd motor neuron are present - Spastic ALS: predominantly clinical features for an affection of the 1st motor neuron and fewer signs of an affection of the 2nd motor neuron - Primary lateral sclerosis (PLS): only clinical features for an affection of the 1st motor neuron are present ALS variants in regional propagation patterns: - Typical form: paresis of the upper or lower extremities or the bulbar region as well as the spread of the paresis to other regions - Flail arm syndrome: primary and dominant paresis of the upper extremities and little or delayed spread of the paresis to other regions - Flail leg syndrome: primary and dominant paresis of the lower extremities and little or delayed spread of the paresis to other regions - Axial ALS: primary and dominant paresis of the trunk muscles and minor or delayed spread of the paresis to other regions - Progressive bulbar paralysis: primary and dominant paresis in the bulbar region and slight or delayed spread of the paresis to other regions

KYSA-6: A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, in Subjects With Refractory Generalized Myasthenia Gravis

Myasthenia gravis (MG) is a chronic autoimmune disease that affects the neuromuscular junction and is characterized by muscle weakness. B cells play a role in MG, and the disease is characterized by the presence of autoantibodies such as anti-AChR and anti-MuSK antibodies. CD-19 target chimeric antigen receptor (CAR) T cells harness the ability of cytotoxic T cells to directly and specifically lyse target cells to effectively deplete both normal and autoreactive B cells in the circulation as well as impacted lymphoid and potentially non-lymphoid tissues. KYV-101, a fully human anti-CD19 CAR T-cell therapy, will be investigated in adult subjects with myasthenia gravis (MG).

A Study to Investigate LDL-cholesterol Lowering With Inclisiran Compared to Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease.

During the screening period study eligibility will be assessed and the participants' individual LDL-C target according to guideline (Mach et al., 2020) will be determined. Among other criteria, at screening, a participant must be on a stable maximally tolerated dose of a HI statin with either atorvastatin ≥40 mg once a day (QD) or rosuvastatin ≥20 mg QD (+/- Ezetimibe [10mg]) for ≥ 4 weeks with which, however, a target LDL-C of < 70 mg/dL is not reached. During the open-label treatment period, all participants, who fulfill the inclusion/exclusion criteria, will be randomized at V1 (Day 1) in a 1:1 open-label fashion to either Inclisiran sodium 300 mg s.c. (administered at Day 1 and Day 90) or to BPA tablets 180 mg p.o. (given once daily). Participants will be required to maintain their background lipid-lowering treatment (maximally tolerated statin dose +/- Ezetimibe) unchanged for the duration of the study. The end of treatment (EOT) is reached at day 150. A Safety-Follow-up call will be conducted 30 days after EOT visit (Day 180). The overall study duration is approximately 190 days but can vary depending on individual screening and the visit windows allowed for the treatment period and EOS visit.

Study to Evaluate the Efficacy and Safety of Subcutaneous Sonelokimab Compared with Placebo in Adult Participants with Moderate to Severe Hidradenitis Suppurativa

A Study to Evaluate the Efficacy and Safety of Subcutaneous Sonelokimab Compared with Placebo in Adult Participants with Moderate to Severe Hidradenitis Suppurativa