Blankenheim , Ahr, Germany

PROPULSION SANTE: Inflammometry to Improve the Diagnostic Trajectory in Situations of Suspected Asthma in Children and Adults

BACKROUND : Asthma is one of the most prevalent chronic diseases worldwide. In Canada, it affects 11% of the population. In Quebec, an estimated 900,000 people suffer from asthma, including 300,000 children. Type 2 eosinophilic inflammation is present in 50% of asthma cases and in 95% of individuals with severe disease, who consume more healthcare resources. This type of inflammation is clinically identified through non-invasive measurements of exhaled nitric oxide (FeNO) and blood eosinophil count (BEC). Asthmatic patients with Type 2 inflammation are at higher risk of asthma attacks and appear to be at risk of accelerated lung function decline, both in adults and children. The presence of Type 2 inflammation predicts a strong response to inhaled corticosteroids (ICS). Currently, post-bronchodilator reversibility and/or bronchial hyperresponsiveness documented via spirometry are the two main approved methods for diagnosing asthma. Bronchial provocation testing is required in 80% of suspected asthma cases, but our population faces a severe lack of access to this test.The average wait time for this 1-2 hour procedure exceeds one year in our three centers. Currently, prioritization is based on the order in which requests are received, with internal referrals given priority over external ones. In Europe, FeNO is already used as a complementary diagnostic tool in primary care, while in Quebec, it is only accessible in severe asthma clinics. Type 2 eosinophilic inflammation is present in 50% of asthma cases and in 95% of severe asthma cases. This inflammation can be identified through non-invasive biomarkers, such as FeNO and blood eosinophil count. Individuals with type 2 inflammation are at higher risk for asthma attacks and are more likely to experience accelerated decline in respiratory function, both in adults and children. However, type 2 inflammation also predicts a strong response to inhaled corticosteroids (ICS).The identification of these markers represents a treatable trait. HYPOTHESIS As a prognostic procedure that identifies a treatable trait, early measurement of inflammatory biomarkers could: 1. Prioritize highly inflamed patients for bronchial provocation testing. 2. Provide personalized therapy based on the inflammation type, with evidence-based recommendations included in the medical reports. 3. Improve the management of asthmatic patients who do not respond to initial treatment, ensuring better access to specialized care. OBJECTIVES For patients ≥6 years old with suspected asthma, referred by non-pulmonologists for diagnostic testing, the study aims to use inflammometry to: 1. Reduce diagnostic delays for high-risk patients with probable asthma and exacerbation risk. 2. Enhance test result interpretation by incorporating inflammometry findings, asthma probability assessment, exacerbation risk, and expected response to anti-inflammatory therapies. 3. Alleviate waiting lists across our three centers. 4. Analyze and optimize the diagnostic pathway for suspected asthma cases in Quebec by generating real-world evidence on the clinical, economic, and environmental benefits of inflammometry. METHODOLOGY For one year, an additional respiratory therapist at each center will conduct diagnostic tests for suspected asthma (spirometry with pre/post-bronchodilator testing or methacholine challenge) requested by non-pulmonologists at the Sherbrooke University Hospital Center (CHUS), CHU Sainte-Justine, and the Montreal Children's Hospital. All patients ≥6 years old on the waiting list will be invited to a clinic visit, where a complementary assessment will be offered. This innovative approach includes: 1. FeNO measurement (exhaled air) 2. Blood eosinophil count (capillary or venous sample) 3. Questionnaires on asthma control and quality of life, completed at baseline and at 4, 8, and 12 months If spirometry is non-diagnostic, bronchial provocation will be prioritized based on inflammatory profile: 1. if ≥1 biomarker is elevated (for those ≥12 years old, FeNO ≥25 ppb or blood eosinophils ≥300 cells/µL; for those aged 6-<12 years, FeNO ≥20 ppb or eosinophils ≥300 cells/µL), the bronchial provocation test will be prioritized (<2-4 weeks). 2. If both biomarkers are low, the scheduling of the provocation test will follow the usual timelines. If spirometry or provocation confirms asthma, additional biomarker data will inform the physician about the risk of asthma attacks. OUTCOMES The primary outcome will be diagnostic delay evolution for high- vs. low-risk asthma patients, analyzed before, during, and after the project. Receiver Operating Characteristic (ROC) curves will be used to assess the diagnostic performance of inflammometry as a potential diagnostic tool, including determining thresholds that could eliminate the need for provocation test. The analyses will be completed by questionnaires evaluating user satisfaction, economic efficiency measures (cost-effectiveness, cost-utility, budget impact), and an environmental impact assessment (measured in kgCO2 emitted by inhalers used when asthma is not diagnosed). IMPACT 1/ Implementation of an evidence-based prioritization system for primary care referrals, substituting the current chronological approach, to reduce wait times for high-risk patients. 2/ Integrating biomarker results with pulmonary function test outcomes will refine their interpretation and better assess the likelihood of an asthma diagnosis, exacerbation risk, and response to anti-inflammatory treatments. 3/The resources allocated by this project will help reduce waitlists. 4/ Real-world evidence from Quebec will be used to improve the asthma diagnostic algorithm, facilitating the integration of inflammometry into asthma diagnosis in the province. This could potentially eliminate 20% of bronchial provocation tests, reducing costs with net-zero financial impact.

TENS Therapy to Reduce Exercise-Induced Pain in Women with Fibromyalgia

Study Design Randomization with minimization will be performed using MinimPy software to ensure group balance, considering the following factors: - Pain intensity, assessed using a pain scale (0-10) - Fibromyalgia severity, assessed using the Fibromyalgia Impact Questionnaire - Age Participants will be informed that different types of TENS stimulation may or may not produce a sensation, and this does not impact treatment effectiveness. Resistance Exercise Protocol The resistance training protocol involves a leg press exercise performed at a 90° starting angle. Participants will undergo a familiarization period, a warm-up, and a repetitions-to-failure (RTF) test to determine their 5-repetition maximum (RM). The Epley equation will be used to predict the 1RM. Participants will then perform two sets of 10 repetitions at 60% of their estimated 1RM, with a 1-minute rest between sets. A kinesiologist will supervise the training session. Data Collection Baseline Assessments: Demographic information (age, gender identity, height, weight, medication) Physical activity level (Physical Activity Questionnaire for Adults) Fibromyalgia severity (Fibromyalgia Impact Questionnaire) Kinesiophobia (Tampa Scale of Kinesiophobia) Treatment expectations (Numerical scale from -100 to 100) Blood pressure Repetitions to Failure Test (RTF) Participants will also complete a digital logbook via REDCap to record their pain levels at the end of the day and 24 hours post-exercise.

A Study of 2 Doses of Ritlecitinib in People 12 Years of Age and Older With Alopecia Areata

The Dragon PLC Trial (DRAGON-PLC)

Primary liver cancer (PLC) is the third most common cause of cancer death worldwide. Surgical resection is the mainstay for a curative approach as contemporary chemotherapy and immune-based therapies only lead to a median survival of 10-14 months. A complete surgical resection increases the median survival to 42 months (range 32-52 months). However, PLC is mainly diagnosed at an advanced stage and >70% of PLC patients are ineligible for an immediate surgical approach. There are different reasons that make a patient ineligible for surgery, one important reason is the risk of liver failure after the surgery due to a small remnant liver. This study aims to improve the oncological, radiological and surgical strategy to allow more patients to undergo liver resection safely, to improve quality of life and to extend overall survival at acceptable costs. Adequate function of the future liver remnant (FLR) is a prerequisite for surgical resectability. This is necessary in order to avoid liver failure after surgery, a major cause of morbidity (38%) and mortality (27%). To mitigate this risk, regenerative strategies based on preoperative calculation of the FLR volume and function are essential. Patients with technically resectable disease but predicted insufficient FLR volume or function are referred to as primarily unresectable or potentially resectable (PU/PR). These patients can undergo strategies that capitalize on the regenerative capacity of the liver which aim to preoperatively increase the FLR volume and function in order to allow surgery. Many of the patients that are primarily unresectable due to an insufficient FLR can become ultimately and safely resectable after the induction of adequate FLR-hypertrophy by the current standard, portal vein embolisation (PVE). However, 25% of patients do not show sufficient FLR growth after PVE and are unable to safely undergo resection. A new approach has been developed to improve this. Combined portal and hepatic vein embolisation (PVE/HVE) has great promise in terms of increasing FLR growth, resection rate (RR), safety and potentially, overall survival. Establishing PVE/HVE as the new standard could result in increased survival and a better quality of life (QoL) for patients.

Impact of Aerobic Exercise on the Anticancer Immune Response in Patients Receiving Cancer Treatment

In recent years, there has been growing interest in the therapeutic role of exercise in the context of oncology. Several murine models have demonstrated a reduction in tumor growth with aerobic exercise, which is partly due to the increased immunogenicity of the tumor microenvironment (TME). Aerobic exercise has the potential to mobilize cytotoxic immune cells, particularly those contributing to anticancer immunity (natural killer cells; NKc, and cytotoxic T lymphocytes; TCD8+), both in healthy individuals and in those living with cancer. In the latter, a session of aerobic exercise induces a transient rise in plasma lymphocytes, followed by their extravasation into inflamed tissues in the hours following exercise. This phenomenon, known as "exercise-immune-enhancement," appears to be heavily dependent on the adrenergic activation triggered by exercise. In other words, NKc and TCD8+ cells are mobilized in response to exercise of sufficient intensity, meaning a minimal physiological threshold must be reached during physical exertion, which should be identified on an individual basis (i.e., the second lactate threshold). However, it is crucial that cytotoxic immune cells mobilized by aerobic exercise can infiltrate the TME and exhibit characteristics that allow them to counter immune evasion mechanisms. Animal studies have shown that aerobic training increases the number of NKc and TCD8+ cells within primary tumors and delays tumor growth, supporting the hypothesis that exercise could stimulate tumor infiltration by cytotoxic lymphocytes acting within the TME. To date, no human studies conducted during treatment have confirmed this hypothesis. The main objective of this study is to determine to what extent Tc and NK cells mobilized by aerobic exercise will exhibit migratory and functional capacity in patients undergoing treatment for curable breast or colorectal cancer. The secondary objective is to compare the effect of a moderate-intensity exercise (MOD) session with an high-intensity interval exercise (HIIE) session on the magnitude of this anti-cancer immune response to exercise and on the phenotypic and functional characteristics of the cells that have been mobilized. The hypothesis is that exercise will promote cell migration, enhancing anti-cancer functionality, suggesting its potential as an adjuvant to immunotherapy. Additionally, higher exercise intensity is expected to increase mobilization of cytotoxic lymphocytes and expression of markers indicating stronger immunotherapeutic potential. Forty-four individuals (aged 40-70) undergoing adjuvant treatment for breast or colorectal cancer will be recruited to participate in a randomized, crossover study with variable block size and counterbalanced design comparing the effect of two exercise modalities (MOD and HIIE), on the migratory and functional capacity of cytotoxic immune cells. An initial visit will be conducted to collect the following variables: resting heart rate and blood pressure, anthropometry, medical history, physical activity habits (questionnaire), gender identity, and aerobic capacity, which will be assessed using a submaximal graded exercise test on a cycle ergometer (modified YMCA). During MOD, participants will complete 32 minutes of cycling at 50% of the power output achieved during the last completed stage of the submaximal test. During the HIIE condition, participants will complete 10 intervals alternating 1 minute of intense effort at a power corresponding to 110% of the final stage completed in the modified YMCA test and 2 minutes of active recovery at 25% of the same stage, for a total duration of 30 minutes. Both experimental conditions are thus equivalent in terms of external effort load. During both exercise sessions, blood samples will be collected before, immediately after exercise cessation, and at 60 and 120 minutes post-exercise for complete blood counts and isolation of peripheral blood mononuclear cells (PBMCs) to assess migratory and functional capacity. Two familiarization sessions will precede the experimental conditions to test the respective prescriptions for MOD and HIIE to ensure that participants can complete the sessions at the required intensity to meet the research objective. A chemotactic gradient migration assay (Transwell assay) will be performed using the thawed PBMCs, and those that have migrated after 4 hours will be collected to characterize NKc and TCD8+ subpopulations and assess cytotoxicity potential using surface and intracellular antibody staining (fluorescence-activated cell sorting [FACS]). The results of this study will help determine the extent to which the TCD8+ and NKc mobilized by aerobic exercise can migrate towards cancer cells, as well as the characteristics associated with anticancer cytotoxicity in individuals undergoing systemic treatment for curable breast or colorectal cancer. This data will help guide larger-scale randomized clinical studies with control groups aimed at confirming the adjuvant therapeutic role of individualized aerobic exercise in individuals undergoing systemic treatment.

A Platform Trial for Gram Negative Bloodstream Infections

BALANCE+ is an adaptive platform trial evaluating multiple treatment options in patients admitted to the hospital due to Gram negative bloodstream infections (BSIs). It focuses on both cross-cutting and subgroup-specific questions, using an open-label, pragmatic design embedded in routine care. BALANCE+ addresses the significant health concern of BSIs, which have high morbidity and mortality rates, exacerbated by the global public health threat of antimicrobial resistance (AMR). With rising resistance rates and limited new drug development, effective treatment strategies for BSIs remain under-researched. BALANCE+ follows the BALANCE trial, which evaluated duration of antibiotic treatment, and aims to further investigate critical questions in managing Gram-negative BSIs. This platform trial will explore various aspects of BSI treatment, including antibiotic de-escalation, oral antibiotic choices, central line management, treatment of specific pathogens, and the necessity of follow-up blood cultures. BALANCE+ is using Bayesian methods without a fixed sample size. Interim analyses will occur after every 1000th patient in each domain, and then for every 200th patient thereafter. The trial will stop if futility or superiority thresholds are met, or if a domain reaches its ceiling sample size (2500 patients for most domains and 4000 for the beta-lactam versus non-beta-lactam domain) without meeting a stopping threshold. A vanguard pilot trial involving over 150 patients at 9 hospitals across Canada confirmed the feasibility of the BALANCE+ trial. The main trial will include patients from the vanguard pilot phase since there has been no major change in the overall study design and domains. The adaptive design allows for interim analyses and adjustments by adding or removing domains as per the statistical analysis plan, enhancing the trial's efficiency and relevance.

A Study of GSK5764227 in Participants With Advanced Solid Tumors

HER2-PET Imaging in HER2-low Breast Cancers

According to the Canadian Cancer Society, it is estimated that there were 28,600 new cases of breast cancer and 5,500 deaths due to the disease in Canada in 2022. Early stage, estrogen receptor-positive (ER+) tumor lesions are normally treated with resection, chemotherapy, and then hormone therapy and have the best prognosis for cure1. However, cases with metastases2, receptor-negative (ER-)3, and/or recurrence4 have a poor outcome and increased mortality. However, overexpression of the pro-oncogene Human Epithelial growth factor Receptor 2 (HER2), with or without ER expression, is linked to more aggressive cancers with poor prognoses5. Thus, ER and HER2 status are two of the most important prognostic factors for breast cancer and are routinely monitored on biopsy and tumor resection samples in pathology. HER2 status is also important to know in a range of cancers, including esophageal,6 gastric,7 ovarian,8 endometrial,9 and lung.10 However, it has been reported that in breast cancer patients with HER2 overexpression treated with a combination of chemotherapy and Herceptin (trastuzumab), a HER2-targeted antibody, the status of a potential recurrence will be HER2- in 43% of cases.11 A receptor status mismatch has been found between primary lesions and metastatic sites in 15% of patients for HER2 at initial workup.12-13 These data show that a substantial number of metastatic and/or recurrent breast cancers have heterogeneous disease, for which conventional primary and locoregional biopsy methods will fail to identify the optimal treatment plan and provide an accurate prognosis. Although the feasibility of taking biopsies from suspected metastatic sites has been demonstrated to monitor the status of distal lesions14, it is difficult or impossible to take biopsy samples from all known and suspected sites for each patient, especially without knowing the precise metastatic status of each patient. This finding therefore highlights the need for a pan-body and non-invasive method of assessment and detection of HER2 for better cancer management and better use of targeted therapies. Several medical imaging modalities allow the detection and monitoring of whole-body cancers. Among these, [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) is routinely used for the initial assessment and staging16 as well as for monitoring of cancer treatment15, and this with high sensitivity and precision. On the other hand, FDG is not a tumor-specific tracer, and its uptake only reflects the relative avidity of a given tissue for glucose. Consequently, the physiological distribution and/or the presence of non-cancerous pathologies can reduce tumor contrast, even mask certain lesions, or lead to false positives17. Trastuzumab and other antibodies targeting HER2 (Kadcyla, pertuzumab, etc.) are commonly used in the clinic and are very effective immunotherapies for the treatment of these very aggressive and previously very difficult to treat tumors. A few groups have already radiolabeled trastuzumab with zirconium-89 ([89Zr]-DFO-trastuzumab), and animal18 and human19 PET imaging studies have been successfully conducted. In 2016, the first data derived from PET imaging of human dosimetry and biodistribution of [89Zr]-DFO-trastuzumab were reported by an American group20,24. Recently, our research group has also succeeded in producing [89Zr]-DFO-trastuzumab with a better molar activity (~25 MBq/nmol) than that reported elsewhere so far21-22. A preclinical protocol of PET imaging with 4FMFES (an ER tracer) and [89Zr]-DFO-trastuzumab in succession on mice bearing ER+ and HER2+ tumors was developed, allowing the detection and identification with high contrast of lesions with different ER and HER2 status21-22. No side effects were detected during the preclinical procedures, indicating that the formulation is adequate. Building on these results and the expertise developed during these projects, we aim to transpose [89Zr]-DFO-trastuzumab PET imaging into the clinic during a phase II study on a cohort of patients with HER2-low cancer (IHC of HER 2 to 1+ or 2+ out of 3)25. More specifically, this imaging protocol aims to assess whole-body HER2 status26 and thus be able to detect cases with heterogeneous disease, in addition to standard locoregional biopsies. Thus, a clinical phase II focusing on the evaluation of a PET/CT protocol using [89Zr]-DFO-trastuzumab in succession to clinically prescribed FDG on patients will be conducted in order to produce the equivalent of a whole body biopsy of HER2 by imaging.

A Study to Investigate the Safety and Efficacy of SAR446523 Injected Subcutaneously in Adult Participants With Relapsed/Refractory Myeloma

The study will be considered ongoing until the last participant last visit has occurred. Participants will be allowed to continue therapy until disease progression, unacceptable AEs, participant or Investigator's request to discontinue treatment.

Transdiagnostic Internet Cognitive-behavior Therapy for Mixed Anxiety and Depressive Symptoms in Postnatal Women

Background. Nearly 20% of women will be confronted with anxiety or depressive disorders during the perinatal period and this may lead to adverse outcomes for both mother and child. Cognitive behavioural therapy (CBT) is the psychological intervention with the most empirical support for the clinical management of anxiety and depressive disorders. Depression and anxiety frequently occur in women during the perinatal period, and there is growing evidence that internet-delivered CBT (iCBT) could be an acceptable and effective intervention. ThisWayUp iCBT Virtual Clinic in Australia has developed a program for postnatal anxiety and depression. As part of a Québec-Ontario collaboration, this research protocol aims to examine the acceptability and efficacy of a French-Canadian adaptation of the postnatal anxiety and depression program. Methods/Design. The investigators propose to conduct a hybrid type 1 randomized clinical trial and implementation study to replicate the findings of the trial conducted in Australia as well as explore barriers and facilitators to potential large-scale implementation. Treatment and control groups. a) adapted postnatal depression and anxiety iCBT program (3 lessons to complete in six weeks) added to treatment-as-usual (TAU); b) TAU. Participants will include women with possible postnatal depression or anxiety as per the Generalized Anxiety Disorder-7 (GAD-7) or the Edinburgh Postnatal Depression Scale (EPDS). The primary outcome measures will be the GAD-7 and the EPDS. Secondary outcome measures will comprise self-reported instruments to evaluate mother-child experience, postnatal depression, psychological distress, suicidality risk, quality of life, treatment satisfaction and service utilization. Statistical analysis. Statistical analysis will follow intent-to-treat principles. A mixed model regression approach will be used to account for between- and within-subject variations in the analysis of the longitudinal effects of iCBT compared to TAU intervention. Moderation analyses will be performed for three sets of moderators: clinical characteristics, previous treatments and sociodemographic characteristics. Additionally, treatment effect sizes will be calculated with Cohen's d. Discussion. The study will deliver important data of efficacy and acceptability to patients, clinicians, and decision-makers to inform the scaling-up of the postnatal iCBT intervention. The benefits to patients could include timely access to services, improved remission rates and health-related quality of life, better long-term outcomes; and to the healthcare system, policy and decision-makers: improved efficiency, optimization of resources, and this to meet the perinatal women and child needs equitably.