Santiago - Recoleta, Chile

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).

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.

PROactive and Early Infliximab Monitoring and OPTimization in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases that entail important morbidity and frequently require high-cost medications such as biologic therapies. Monoclonal antibodies against tumoral necrosis factor (anti-TNF) are effective and can modify the progressive course of IBD. In Chile, given the high cost of anti-TNF therapy, this medication is provided by a national program with universal coverage. Unfortunately, a significant proportion of IBD patients never respond (primary non-response, PNR) or experience loss of response (secondary loss of response, SLR) to anti-TNF within the first year of therapy and current evidence support that the complex pharmacokinetics of anti-TNF is involved in both scenarios. Additionally, low trough levels (TL) are associated with the development of antidrug antibodies (ADA) which reduce anti-TNF efficacy and can cause anaphylactic reactions. This is particularly relevant for intravenous infliximab (IFX) which is usually indicated in IBD patients with acute severe disease not responding to iv corticosteroids. Therefore, IFX is frequently dose escalated in patients based on clinical parameters that are thought to be related to drug clearance with conflicting evidence supporting this strategy. Several studies have demonstrated that IFX TL between 7-20 mcg/ml at week 14 of treatment is a strong and independent predictor of therapy response. Furthermore, IFX dashboard-guided dose optimization based on clinical and pharmacokinetic (PK) parameters using adaptive Bayesian modeling have demonstrated to be more precise that empirical adjustments based on the clinician intuition alone. Therefore, the goal of this study is to analyze whether early therapeutic drug monitoring (TDM) and dose adjustment based on a Bayesian model (iDOSE) in CD and UC patients initiating IFX, increases the proportion of patients with therapeutic levels (7-20 mcg/ml), reducing immunogenicity and consequently increasing the rate of disease remission. A prospective multicentric randomized clinical trial (RCT) of Chilean adult IBD inpatients starting IFX due to moderate-to-severe disease refractory to corticosteroids will be carried out. Patients will be randomized 1:1 to: 1. - Dashboard-guided dosing arm. Patients will undergo proactive TDM during induction (TL at IFN 2 and 3) with dose adjustment based on iDOSE. 2. - Standard dosing arm. Patients will receive dose adjustment based solely on clinical parameters. Both groups will be followed-up after induction with clinical visits, TL and ADA at week 14 (INF 4), 26 and 52. Researchers expect that a higher proportion of patients in the dashboard-guided dosing arm will achieve therapeutic TL of IFX (7-20 mcg/ml) at week 14 of treatment (Primary outome). Secondary outcomes will include clinical and laboratory parameters related to therapy response at week 52 of treatment, proportion of patients experiencing PNR and SLR, patients developing ADA, as well as, adverse events, hospitalization and surgery

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

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.

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 Study of Rilvegostomig in Combination With Fluoropyrimidine and Trastuzumab Deruxtecan as the First-line Treatment for HER2-positive Gastric Cancer

The purpose of this study is to assess the efficacy and safety of rilvegostomig in combination with fluoropyrimidine and T-DXd (Arm A) compared to trastuzumab, chemotherapy, and pembrolizumab (Arm B) in HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma participants whose tumors express PD L1 CPS ≥ 1. Rilvegostomig in combination with trastuzumab and chemotherapy will be evaluated in a separate arm (Arm C) to assess the contribution of each component in the experimental arm. This study will be conducted at up to 200-250 sites globally in approximately 25 countries.

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.

Pharmaco-proteomic Platform to Evaluate Drug Interactions in Liver Transplant Patients

The aim of this project is to enhance the ability to forecast kidney failure for liver transplant patients in the ICU by developing a computer platform that integrates mathematical models of drug interactions, proteomics, and clinical data. This integrated platform enables the prediction of the development of AKI in patients who have undergone OLT. Through the integration of mathematical models, the platform captures complex interactions between multiple drugs and proteomics data from patients, contributing to an improved predictive capacity for AKI outcomes. By leveraging proteomic insights, personalized therapeutic interventions can be devised, promoting safer and more effective treatments. This research seeks to empower medical professionals with comprehensive information to navigate the complex landscape of drug interactions and personalized treatment strategies, ultimately contributing to improved patient outcomes and healthcare practices in the realm of liver transplantation.

A Study of Zasocitinib in Adults With Psoriatic Arthritis Who Have Not Taken Biologic Medicines