Santiago - Recoleta, Chile

Rollover Study for Participants Previously Enrolled in Clinical Trials of Povorcitinib

Effect of Continuous Prolonged Prone Position Versus Intermittent Daily Prone Position in ARDS

Acute Respiratory Distress Syndrome (ARDS) is a severe condition with a 40% mortality rate. The management of ARDS still relies largely on supportive therapy. The cornerstone of this support is protective mechanical ventilation to prevent ventilator-induced lung injury (VILI). For patients with moderate-to- severe forms of ARDS, specifically mechanically ventilated patients with PaO2/FiO2 ratios below 150, the use of prone position has shown to be a fundamental intervention which became one of the most relevant pillars of the ICU management during the Covid-19 pandemics. Several studies have shown that prone position not only improves oxygenation, but can attenuate the mechanisms of VILI, which would explain its benefit in terms of mortality. The physiologic benefits of prone position are progressive along time, but they can be lost rapidly after returning to supìne position. Since the publication of the landmark PROSEVA study (Guerin 2013), which showed that ventilating patients in prone position decreased mortality, the standard approach to prone position has been the use of daily sessions of 16 to 20 hours. With this approach most patients usually require 3 to 4 prone sessions (intermittent daily prone position). However, due to the excessive workload of ICU staff during the Covid-19 pandemics, several centers decided to extend the sessions beyond 24 hours to decrease the frequency of position changes in patients with Covid-19 associated ARDS. Several centers reported their experience with prolonged sessions showing that it was feasible and that the rate of adverse events appeared to be similar to those previously reported with the standard daily sessions. The largest experience reported up to now was a retrospective study which included 417 patients from 15 centers in Chile, where a continuous prolonged prone position was applied as a nationwide strategy (Cornejo 2022). Most patients required a single prone session of 4 (3-5) days. Although the study lacked a control group, the mortality and rate of adverse events was rather low compared to other series of patients with similar characteristics. A non-randomized controlled study from 3 hospital in US even showed that compared to patients treated with standard prone sessions (< 24 hours), patients treated with prolonged sessions had a lower risk of mortality (Okin 2023). However, other reports have shown conflicting results regarding the potential benefit associated to prolonging prone position sessions beyond 24 hours. Recent guidelines have acknowledged that the optimal duration of prone position sessions is unknown and must be further investigated (Grasselli 2023). Prolonging prone position sessions may ensure that this lung protective intervention is maintained throughout the acute phase of ARDS. The goal of the present study is to compare the effects of a continuous prolonged prone position versus an intermittent daily prone position on mortality and other relevant outcomes, as well as on the incidence of adverse events potentially related to prone position, in mechanically ventilated patients with moderate-to-severe ARDS. The study will be a randomized, multicenter, two-arm parallel-group, investigator-led clinical trial with allocation concealment and intention-to-treat analysis. Patients allocated to the experimental arm (prolonged prone position) will receive prone position sessions for a minimum of 48 hours, which will be further extended until PaO2/FiO2 is ≥ 200, or until reaching the maximum of 120 hours. Patients allocated to the control arm (intermittent prone position) will receive prone position sessions for a minimum of 16 hours and a maximum of 24 hours. In both groups prone sessions may be repeated if PaO2/FiO2 ratio falls below 150 after being returned to supine position during the first 7 days (intervention period).

Study of Mixed Vaccination Schedules With a 21-valent Pneumococcal Conjugate Vaccine and a 20-valent Pneumococcal Conjugate Vaccine in Healthy Infants From Approximately 2 Months of Age

Fluid Intolerance Signals as Safety Limits to Prevent Fluid-induced Harm During Septic Shock Resuscitation

Fluids are the first-line hemodynamic therapy during septic shock resuscitation, restoring tissue perfusion by effectively increasing cardiac output and oxygen delivery. Nevertheless, resuscitation fluids can be seen as a double-edged sword since they have a narrow therapeutic index. In the one hand, insufficient fluid administration can perpetuate hypoperfusion, leading to irreversible tissue hypoxia, while excessive fluid administration can lead to fluid-induced harm. The extreme scenario of this condition, fluid overload, has been consistently associated with worse clinical outcomes, including increased risks of prolonged mechanical ventilation, acute kidney injury and mortality. As an eminently retrospective diagnosis, it may underestimate the importance of timely recognition of fluid-induced harm during the resuscitation period and could shift clinicians' efforts to treatment rather than prevention. Thus, identifying organ-specific venous congestion signals early on during the resuscitation process is desirable and could avoid these adverse outcomes. Recent studies have shown that venous congestion signals are present even during the first day of ICU admission. The investigators hypothesized that in critically ill patients with septic shock, a fluid resuscitation strategy that integrates fluid intolerance signals as safety limits will prevent fluid-induced harm, without compromising hypoperfusion resolution, compared to a standard resuscitation strategy. To confirm this hypothesis, the investigators propose a multicenter prospective randomized controlled study in 62 critically ill patients with septic shock, comparing two strategies for conducting fluid resuscitation, aiming to decrease fluid-induced harm. One strategy will follow the standard of care, while the other will rest on real-time ultrasound-based monitoring of fluid intolerance signals. The latter approach will allow clinicians to limit fluid administration when potentially deleterious signals appear. The impact of both strategies on fluid-induced harm will be assessed by the evolution of key organ function biomarkers, namely lungs, heart, and kidneys during the 6-hour study period. Perfusion dynamics will be assessed by capillary refill time and arterial lactate kinetics during the study period. Patients will receive general monitoring and management according to ICU standards. Patients will be followed-up for 28 days for other relevant outcomes.

A Phase 3, Placebo-controlled, Double-blind Study Assessing Rocatinlimab in Prurigo Nodularis

Lighthouse Parenting Nanai: a Mentalization-based Group Therapy for Caregivers with History of Trauma

This study is a feasibility randomized controlled trial designed to assess the Lighthouse Mentalization-Based Treatment Parenting Program (Lighthouse MBT-P) for parents who are at risk of maltreating their children. The Lighthouse MBT-P program is specifically tailored for parents with a history of trauma and aims to enhance their mentalizing abilities-helping them better understand and reflect on their own and their children's emotions and thoughts. By improving these skills, the program intends to strengthen parent-child relationships, reduce parenting stress, and ultimately decrease the risk of child maltreatment. Study Design: The study is being conducted at Diego Portales University in Santiago, Chile, with a total of 60 participants who will be randomly assigned to one of two groups: the intervention group receiving the Lighthouse MBT-P program and a control group receiving standard psychoeducational support. The intervention will consist of weekly 2-hour group sessions over 12 weeks, where participants will engage in psychoeducation and reflective discussions, facilitated by trained psychologists. These sessions aim to provide parents with the tools to improve their emotional regulation, understand their children's needs better, and develop healthier parenting practices. Study Phases: Cultural Adaptation: The Lighthouse MBT-P program has been culturally adapted to ensure its relevance and effectiveness within the Chilean context. This phase involved consultations with local experts, community stakeholders, and pilot testing with a small group of parents to refine the intervention content and delivery methods. Clinician Training: Therapists who will deliver the Lighthouse MBT-P program have completed a comprehensive training program, including a three-day workshop and ongoing bi-weekly supervision by an MBT specialist. This training ensures that the intervention will be delivered consistently and effectively, adhering to the principles of mentalization-based treatment. Intervention Delivery: The intervention group will participate in the Lighthouse MBT-P sessions, focusing on enhancing parental mentalizing abilities. The content will cover topics such as emotional regulation, understanding children's behaviors, and managing stress in parenting. Sessions will be conducted online, allowing for greater accessibility for participants. Data Collection: Data will be collected at multiple time points, including baseline, post-intervention, and follow-up, to assess the feasibility and acceptability of the program, as well as preliminary indicators of its effectiveness in reducing parenting stress and improving parent-child relationships. Analysis and Interpretation: The data collected will be analyzed using both quantitative and qualitative methods to determine the feasibility of the program and to identify any barriers or facilitators to its implementation. The results will inform decisions about whether to proceed with a full-scale randomized controlled trial and guide any necessary adjustments to the program. Significance: This study addresses a critical gap in the availability of trauma-informed, attachment-based interventions for parents at risk of child maltreatment in Chile. By evaluating the feasibility of the Lighthouse MBT-P program, this research aims to provide a foundation for larger-scale interventions that could significantly impact the prevention of child maltreatment and improve the well-being of vulnerable families.

Dose Range Finding Study to Assess Efficacy and Safety of Tozorakimab in Adults With Uncontrolled Asthma on Medium-to-High Dose Inhaled Corticosteroids

Early Inflammatory Bowel Disease Progression

Inflammatory bowel disease (IBD), comprising Crohn ́s disease (CD) and ulcerative colitis (UC), is an idiopathic inflammatory condition of the gastrointestinal tract which is characterized by alternating periods of active disease and remission. IBD is often progressive and associated with significant morbidity. A common endpoint for a progressive course of CD or UC is the need for treatment escalation; initially with immunomodulators and subsequently - if disease activity persists - with biologic therapy or surgery. Early use of biologic therapy improves clinical outcomes and can prevent complications such as strictures, fistulae or severe and progressive disease, obviating need for surgery. The success of early initiation of biologic therapy is most likely related to a therapeutic "window of opportunity" for the implementation of effective therapies in patients with rapidly progressive disease. However, indiscriminate use of biologic therapy would entail exposure of IBD patients with indolent disease to unnecessary expensive treatments and their associated side effects. Unfortunately, the need for biomarkers to reliably guide IBD treatment in a timely manner remains unmet. The literature supports a relevant role for host-gut microbiota interactions in IBD progression. This interaction is often mediated by microbial-derived metabolites. Fecal short chain fatty acids (SCFA) and secondary bile acids (BA) are remarkable examples of such metabolites. They are reduced in IBD patients, and in animal models are capable of mitigating exaggerated host immune response with consequent improvement in gut inflammation. Recently, researchers have started to explore the capacity of taxonomic and metabolomic signatures to predict meaningful clinical outcomes in IBD. Given the role of gut microbes and their metabolites in immune response, they are plausible biomarkers of IBD progression and therapy response. However, most of the studies exploring biomarkers for IBD include patients with longstanding IBD or previous failure to first-line therapies, rendering their results incompatible with early risk stratification. An inception cohort of newly diagnosed IBD patients integrating clinical, transcriptomics, microbial and metabolomic profiling can overcome these limitations, increasing the sensitivity to detect biomarkers of progressive disease before the therapeutic "window of opportunity" has passed. In the clinical setting, such biomarkers would enable clinicians to maximize therapeutic efficacy of biologic agents and implement as early as IBD diagnosis, a cost-effective therapeutic approach. The objective of this project is to establish whether an impaired gut microbial capacity to synthesize SCFA and secondary BA at the time of IBD diagnosis can predict early need for treatment escalation (progression). To achieve this objective, our specific aims are: 1) To define the gut taxonomic and metabolomic profiles of newly diagnosed IBD patients and their associations with early clinical outcomes. The investigators will recruit an inception cohort of treatment-naïve IBD patients before undergoing their first diagnostic colonoscopy. The global metabolome, including SCFA and secondary BA abundance will be analyzed, as well as the taxonomic profile of fecal samples and mucosal-luminal interface (MLI) aspirates obtained at colonoscopy. The identified "omics" signatures will be correlated to the need for treatment escalation to derive predictive biomarkers of progressive IBD course. 2) To establish the impact of gut microbial dysbiosis and dysmetabolism of SCFA and BA of newly diagnosed IBD patients on mucosal inflammation and host gene expression. Analysis of taxonomic and metabolomics profiles obtained in MLI samples will be integrated to mucosal host gene expression analysis to identify host transcripts affected by differential SCFA and secondary BA abundance. 3) To quantify the in vitro capacity of gut microbiota of newly diagnosed IBD patients to synthesize SCFA and secondary BA. Gut microbiota from IBD patients will be inoculated into a batch bioreactor which closely mimics the gut luminal environment. The investigators will then perform serial measurements of SCFA, BA and bacterial abundance, estimating rates of metabolite synthesis. The metabolic activity will be correlated to in vivo metabolite abundance and clinical outcomes. The investigators anticipate that IBD patients requiring early therapy escalation (progressors) will have decreased in vivo concentrations of SCFA and secondary BA, and an impaired in vitro microbial capacity to synthesize these compounds compared to patients not requiring therapy escalation. The investigators also expect to find that the taxonomic and metabolomic signatures of these patients have a distinct impact on host gene expression. Our comprehensive approach will allow us to identify reliable biomarkers which can be exploited in the clinical setting to guide early biologic treatment using a 'personalized medicine' approach and will provide novel insight into the biologic mechanisms underlying need for premature therapy escalation as a proxy of early progressive and aggressive course in IBD.

An Ophthalmic Safety Study in Patients With Breast Cancer

This is a multicentre study assessing the ophthalmic safety in patients who are participating in a qualifying study. The study will include two cohorts of at least 60 individuals each. To be able to account for events associated with aging, worsening of pre-existing conditions, etc., ophthalmic study assessments will be performed in parallel in two cohorts at the same timepoints. The duration of the study assessment period will be approximately 12 months. Longer duration of the study would result in additional patient burden.

A Phase III Renal Outcomes and Cardiovascular Mortality Study to Investigate the Efficacy and Safety of Baxdrostat in Combination With Dapagliflozin in Participants With Chronic Kidney Disease and High Blood Pressure

The purpose of this study is to investigate the efficacy, safety, and tolerability of baxdrostat in combination with dapagliflozin, compared with placebo and dapagliflozin, in reducing the risk of the composite of > 50% decline in eGFR, kidney failure, or CV death, in individuals with CKD and HTN. This study consists of a 4-week dapagliflozin Run-in Period for participants untreated with SGLT2i at screening, and a double-blinded period where participants will receive either baxdrostat/dapagliflozin or placebo/dapagliflozin. Site visits will take place at 2-, 4-, 8-, 16-, 34, and 52-weeks following randomisation. Thereafter visits will occur approximately every 4 months. The study closure procedures will be initiated when the predetermined number of primary endpoint events is predicted to have occurred ie, the PACD. All randomised participants including any participants who have prematurely discontinued study intervention will be scheduled for a SCV within a few weeks of the PACD. This period can be extended by the Sponsor. In case of premature discontinuation of blinded study intervention, participants will continue in the study and receive dapagliflozin 10 mg, unless the participant meets dapagliflozin specific discontinuation criteria. If study intervention is temporarily or permanently discontinued, the participant should remain in the study, and it is important that the scheduled study visits (including the PTDV for participants with permanent discontinuation of study intervention) and data collection continue according to the study protocol until the SCV.