Engels Saratov Region, Russian Federation

Apremilast Pediatric Study in Children With Active Juvenile Psoriatic Arthritis

Spondyloarthritis: Inducing Drug-free Remission by Early TNF-alpha Blockade

SPARTACUS will have several achievable goals: 1. To show superiority of early treatment of pSpA patients with bDMARDs as compared to standard of care. In current practice, TNFi, the predominant bDMARDs in SpA, are only reimbursed in a restricted number of indications: they can be prescribed for axial disease (axSpA) and for the specific pSpA-entity, psoriatic arthritis (PsA); however, even in PsA, they are only reimbursed for longstanding, erosive disease, when patients have already failed (multiple) csDMARD(s). In patients with pSpA without psoriasis, rheumatologists can only prescribe csDMARDs, because TNFi are still off-label despite the overall good efficacy observed in several proof-of-concept studies, incl. one phase 3 trial (Ability-2). For this subgroup of patients, the unmet need is therefore still unacceptably high. Moreover, the patients included in Ability-2 reflected the current step-up treatment paradigm: patients already had longstanding disease (symptom duration of approx. 7 years) and had used (and failed) conventional treatment options before trial entry (99% prior use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), 69% prior csDMARD use). In this population, a statistically significant difference between adalimumab and placebo was observed, but clinical remission rates remained somehow disappointing with only 33% of patients reaching the predefined remission outcome after 3 years of continuous adalimumab use. Until recently, no data were available regarding the treatment of early pSpA with bDMARDs. To address this knowledge gap, we designed a proof-of concept study to explore the therapeutic potential of TNFi in patients with pSpA with very short symptom duration, the CRESPA-trial. In this study, all patients had a symptom duration of less than 12 weeks: they were randomized to receive either immediate TNFi therapy (golimumab) or placebo. In summary, the results of this trial demonstrated that after 24 weeks of treatment, complete clinical remission could be achieved in 75% of golimumab-treated patients versus only 20% in patients treated with placebo (thus refuting the perception that a large majority of pSpA patients would go in spontaneous clinical remission). Due to the placebo-controlled design, the CRESPA trial did not provide any data on the percentage of patients that would have achieved clinical remission while on standard-of-care "csDMARD Step-up" treatment. The design of the SPARTACUS head-to-head trial will allow us to evaluate superiority of the new approach to current practice. 2. To delineate the window of opportunity for intensive treatment of pSpA: a transient time frame in which a disease is more susceptible to treatment. In the proof-of-concept CRESPA trial, all included patients had a symptom duration of less than 12 weeks. In these patients very high clinical remission rates were observed when patients were immediately treated with a TNFi. Interestingly, when the bDMARD treatment was interrupted after reaching sustained remission, 53% of patients remained in drug-free remission at long-term follow-up, providing preliminary evidence for the "window of opportunity" hypothesis: by effectively tackling pSpA (with bDMARDs) in a very early phase of the disease, drug-free remission might be an achievable goal in a significant number of patients. However, the CRESPA-trial does not allow to generalize the findings to pSpA patients with longer symptom duration. Moreover, the above-mentioned extension of the Ability-2 study would suggest that patients with a symptom duration of multiple years would have lower remission rates and would need chronic, life-long bDMARD treatment. The SPARTACUS trial will still focus on early treatment of pSpA (symptom duration <12 months), but the stratification of patients according to symptom duration (<3 months (identical to the CRESPA trial) versus between 3 and 12 months) will allow us to explore the exact time frame in which a window of opportunity is applicable. The goal is to demonstrate that drug-free remission is a feasible outcome when an early intensive treatment strategy is adopted and to delineate the window of opportunity (in terms of symptom duration) in which such a remission-induction strategy is successful, leading to significant health economic benefits. 3. To unravel new biomarkers of therapy response using cutting-edge single cell technology. In the CRESPA trial, we observed that despite the fact that 53% of patients were able to achieve drug-free remission, a significant proportion nevertheless relapsed. In this small proof-of-concept study, we were not able to detect significant predictors or remission or relapse. Also, 18% of patients did not achieve sustained clinical remission, but nevertheless experienced a significant improvement of signs and symptoms; in these patients long-term treatment was necessary. These results indicate that clinical response to TNFi is heterogeneous and underscores the need for biomarkers that can identify at baseline different pathogenic subsets that are associated with the (lack of) response to a TNFi. The recent introduction of new procedures such as ultrasound-guided synovial biopsy sampling in our early arthritis clinic has permitted to access synovial samples of virtually all peripheral joints (incl. wrists and small finger joints). By using innovative and unbiased tools recently developed in the area of single-cell analyses (RNA-sequencing and epigenetic profiling), we will obtain profound insights into the cellular heterogeneity of these unique patient samples. 4. To determine health-economic and societal impact of early, intensive bDMARD treatment of patients with recent-onset pSpA (compared to the currently reimbursed csDMARD Step-up strategy). A unique feature of SPARTACUS is that clinical trial and biomarker discovery will be coupled to calculation of the health-economic benefits of such an approach. We aim to determine from a healthcare and a societal perspective, the 2 years´ cost-utility, as well as a model-based lifelong incremental cost-utility of the innovative strategy compared to usual care. Uncertainty analyses will be performed and budget impact for the Belgian healthcare and social security (work disability) system will be calculated. Consistent with the increased call for transparency in health economic modelling, we aim to make our model available as a semi-open source model. 5. To increase awareness among referring physicians (general practitioners, other specialties that may evaluate patients with early SpA) and patient-advocacy groups about the value of early recognition and treatment in rheumatology. It is still a great challenge to diagnose patients in an early stage of their disease. The delay between symptoms and diagnosis in SpA is still several years. As discussed above, it has been shown that in later stages of the disease, the treatment effect (even with bDMARDs) may be less impressive and chronic therapy is needed without possibility of drug withdrawal (leading to a high socioeconomic burden). The broad set-up of SPARTACUS across health institutes in Flanders will greatly facilitate the awareness and direct implementation of early arthritis strategies among physicians. Finally, results from SPARTACUS will provide evidence that will facilitate discussions with patients about treatment choices and ensure realistic treatment expectations and optimal health behaviour in patients with early pSpA.

A Study to Investigate the Efficacy and Safety of Anifrolumab Administered as Subcutaneous Injection and Added to Standard of Care Compared With Placebo Added to Standard of Care in Adult Participants With Idiopathic Inflammatory Myopathies (Polymyositis and Dermatomyositis)

Program to Assess Adverse Events and Change in Disease Activity of Oral Upadacitinib in Adult Participants With Moderate to Severe Systemic Lupus Erythematosus

The Belgian Endothelial Surgical Transplant of the Cornea

The current problem concerns variability in the provision of corneal endothelial keratoplasties available to patients in Belgium. Some patients receive DSAEK and some (albeit fewer) receive DMEK. Currently the type of corneal graft that a patient receives depends on the treating surgeon opinions. In this study 220 patients in 11 surgical centres will be recruited and allocated to one of the two surgical options. Both the Ultrathin DSAEK and DMEK grafts will be prepared by corneal banks in the University Hospital of Liege and University Hospital of Antwerp respectively. Patients will be examined preoperatively and postoperatively at 3, 6 and 12 months. Clinical information such as best-corrected visual acuity and refraction will be collected as well as quality of life information based on the EQ-5D-5L and the VFQ 25 assessment tools. These data be used to compare the interventions both on the clinical level as well as from the patient perspective.

Testing the Value of Novel Strategy and Its Cost Efficacy in Order to Improve the Poor Outcomes in Cardiogenic Shock

The EURO SHOCK trial tests the novel use of early deployment of mechanical support device in Cardiogenic Shock (CGS) in a randomised, strategy trial, with evidence of benefit or otherwise measured by recording hard clinical end-point outcomes. Extra Corporeal Membrane Oxygenation (ECMO) is already used in CGS. This is therefore not a novel therapy. It is the use of ECMO early in the development of CGS that is the novel aspect of this project. The Investigators will test whether a strategy of very early ECMO can ameliorate the rapid decline that many CGS patients suffer. The value of deploying a clinically used and approved device prospectively and early in the natural history of CGS compared to standard practice has not been tested before and will be the basis of the EURO SHOCK project. This trial itself will be a prospective randomized, open label, design study that will compare two groups of patients: Both will receive appropriate percutaneous coronary intervention (PCI) as is current practice as they arrive at the hospital. 1. Group 1 will receive immediate PCI + standard care (pharmacological support). 2. Group 2 will receive immediate PCI plus support with early peripheral veno-arterial ECMO + standard care (pharmacological support). The Investigators will also compare the cost-effectiveness of early VA-ECMO, as compared to current standard of care. EURO SHOCK will also evaluate novel CMR protocols in these unwell patients, and also whether systems of urgent flagged transfer of the unwell patient is practical and beneficial. The Investigators will determine whether there are biological and ECG markers that predict worse patient outcomes, which could thus help select most appropriate patients for expedited treatments (the patient is only transferred if needed). Although at the centre of the project there is a randomised trial, other important objectives will therefore be delivered. The research study will additionally focus, through a-priori, post-hoc analyses, on higher risk and vulnerable sub groups such as the elderly (>75 years) and females, the importance of site of infarct and on those with multi-morbidities such as diabetes. These post-hoc data will be published separately. The trial will include patients with out of hospital cardiac arrest (OHCA) who have documented return of spontaneous circulation (ROSC) but with certain caveats (see exclusion criteria). The primary outcome is the all-cause mortality at 30 days following admission with acute coronary syndrome with cardiogenic shock. Key secondary outcomes will include all- cause mortality or admission with heart failure at 12 months, all-cause mortality at 12 months and admission to hospital with heart failure at 12 months. A cornerstone of this research programme will be to determine the cost-efficacy of ECMO in this setting. Cost benefit will be measured both immediately and in the longer term testing for example any impact of need for heart failure therapies. This will be undertaken with evaluations of the cost-effectiveness of the device and evaluation of quality of life using the EuroQuol-5D-5L and the Minnesota Living with Heart Failure Questionnaire. The EUROSHOCK trial will also include the following sub-studies: 1. Cardiovascular MRI: Cardio-Renal Imaging Sub-study using novel shortened, non-breath-holding protocols. 2. Platelet Function Sub-study designed to access the impact of novel ECMO coatings on platelet activation. The programme will be developed and run through a carefully thought through management structure comprising 8 separate but interlinked work programmes (each targeted at one aspect of the project and headed by an experienced clinical trialist or trial manager) and involve the dissemination of results through a designated dissemination work package. Attention to translating the results to subsequent on-the-ground patient care will be an important aim for the management and dissemination team, and will involve patient support groups, professional societies and information delivered directly to the medical and non- medical staff caring for CGS patients.