Longeville Les St Avold, France

A Multiple Ascending Dose Study of DT-216P2 in Patients With Friedreich's Ataxia

Safety, Tolerability and Efficacy of Intravitreal KIO-104 in Patients With Macular Edema

In Part A of the study, the safety and efficacy of up to three doses (administrations) of KIO-104, administered every 2 weeks, will be investigated in 2 possible dose cohorts. Cohort 1: Low dose KIO-104 administered to the study eye Cohort 2: High dose KIO-104 administered to the study eye Part B of the study will investigate the safety and efficacy of up to three doses (administrations) of KIO-104 with 2 different dosing regimens (every 2 weeks or every 4 weeks), in participants with macular edema at a dose selected from Part A. Cohort 3A: KIO-104 administered to the study eye every 2 weeks Cohort 3B: KIO-104 administered to the study eye every 4 weeks

Evaluation of the Safety and Tolerability of Ocular Lubricants

This study will be conducted in 2 stages. In Stage 1, subjects will attend a total of 10 scheduled visits: one Screening visit, four Investigational Product visits, four 12-hour Follow Up visits (one for each Investigational Product visit), and an Exit visit. At each Investigational Product visit, subjects will receive one drop of the investigational product in each eye (2 drops total), as randomized. The first Investigational Product visit will occur 1 to 7 days after the Screening visit. A washout period of 2 to 7 days will separate each Investigational Product visit. Total individual duration of participation in Stage 1 will be 8 to 34 days. The planned enrollment for Stage 1 is 72 subjects. At the conclusion of Stage 1, an interim analysis will be conducted to help determine potential adaptations to the study design for Stage 2. This study will be conducted in Australia.

A Phase 1 Trial of ERX-315 in Participants With Advanced Solid Tumors

The goal of this open-label, dose escalation and cohort expansion Phase 1 clinical trial is to determine the safety, tolerability and pharmacokinetics of ERX-315 in patients with advanced solid tumors, who have progressed on prior approved systemic therapies. Participants will receive ERX-315 as an intravenous (IV) injection twice a week, over 21-day cycles.

Personalised Immunotherapy Platform

The Personalised Immunotherapy Program (PIP) is a multicenter biomarker discovery and validation program of multi-omic biomarker based predictive models which aim to identify patients with immunotherapy resistant disease. PIP developed predictive models in retrospective setting, with validation within a prospective clinical observational study. Immune checkpoint inhibitors targeting the cytotoxic T-cell lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) receptors have revolutionised the treatment of advanced melanoma, resulting in long-term durable responses and a 5-year overall survival of 52% with combination immunotherapy. However, clinical benefit is not universal, and half of these patients do not respond. Therefore, there is an urgent need for clinically validated biomarkers which can identify patients who are at high risk of not responding to standard-of-care immunotherapies and determine which emerging clinical trial agent is most appropriate for a particular patient's disease. Researchers performed mutation, gene expression and tumour immune profiling on tumour biopsies from melanoma patients treated with anti-PD-1 monotherapy or combined anti-PD-1 and anti-CTLA-4 therapy. From this dataset PIP has developed predictive models to identify patients with immunotherapy resistant disease. The subsequent PIP-PREDICT is a prospective clinical study that enrols advanced cancer patients who are eligible to receive approved immunotherapies. PIP testing and biomarker reporting is used to screen potential patients. Each patient enrolled in the study receives an individual PIP Biomarker Report, which is presented as part of the established Biomarker Multidisciplinary Team (MDT) meeting of clinical oncologists, pathologists, molecular biologists, trials nursing, PIP, and biospecimen staff on a fortnightly basis. PIP-PREDICT has a primary goal of determining the accuracy of biomarker predictions from PIP prospectively within oncology clinics. Secondary goals include assessing the feasibility of biomarker assay workflows within diagnostic providers, conducting a cost-benefit ratio analysis, evaluating the effect of biomarker reports on treatment selection within multidisciplinary teams (MDTs), and performing a post-implementation analysis of personalised immunotherapy biomarker reports in treatment decision making.

Digital Health Technology for People With Mitochondrial Disease

Feasibility study Baseline measurements taken at: week 0 = pre-intervention, Outcome measurements taken at: week 9 = post-intervention assessment Feasibility outcomes: 1. the percentage of participants who enrol in the study from the eligible pool 2. percentage of dropouts over the study duration 3. Compliance to the exercise program and use of DHT: - daily step count goal met from Garmin smart watch data over 56 days expressed as a percentage. - weekly intensity minute's goal met from Garmin smart watch over 8 weeks expressed as a percentage. - Strength training adherence (from exercise diary) expressed as a percentage of the prescription (3 sessions per week over 8 weeks or 24 planned sessions). - Participation in telehealth sessions, expressed as a percentage of the overall prescription (8 telehealth sessions over the 8-week intervention). - Wearing of the smart watch (Garmin) for 8 consecutive weeks (56 days), expressed as a percentage of total wear time (24 hours a day, 7 days a week (excluding showering and recharging of device). Compliance is defined as having met 75% or greater of prescribed activity. Acceptability outcomes will be extracted from post-program questionnaires. Secondary outcomes: - 10 Meter Walking Speed - assesses walking speed in meters per second over a short duration. - 6-Minute Walk Test - walking endurance, distance walked in meters over 6 minutes. - 5 Time Sit to Stand - lower limb strength, time in seconds taken to perform 5 sit to stands from a standard height chair (43 to 45cm). - Grip Strength - hand isometric grip strength contraction held for 3-5 seconds, measuring grip strength in kilograms. - Berg Balance Test - 14-item scale designed to measure balance, scored out of 56. - Fatigue Impact Scale - self-reported questionnaire evaluating the effect of fatigue on three domains of daily life: cognitive functioning, physical functioning, and psychosocial functioning, 40 items, each scored 0 (no problem) to 4 (extreme problem), providing a continuous scale of 0-160. - Newcastle Mitochondrial Disease Adult Scale - rating scale to monitor the progression of a PMD. Sections 1 & 2 are self-rated while section 3 is rated by a neurologist. Home Exercise Program All participants will be provided with a structured home exercise program which is customised according to the participant's baseline activity measures obtained from smart watch data over 1 week pre-intervention (week 0). This home exercise program is undertaken using the supplied smart watch (Garmin), Physitrack app and elastic bands. An education session on how to use the training equipment will be conducted week 1- start of intervention appointment at Neuroscience Research Australia (NeuRA). A narrated video of the exercise program will also be sent to participants via email through the Physitrack app. A hard copy version of the exercise program will be supplied to participants along with an exercise diary at the week 1 start of intervention appointment. The home exercise intervention will last 8 weeks and consist of: 1. A daily step target goal. 2. A weekly intensity minutes target goal. 3. Major muscle group strengthening using the supplied equipment. Daily step target: Participants will attempt to increase their daily step count by 10% each week from baseline, until an increase of 50% is achieved at week 5. This volume will be then maintained or increased as tolerated for the remaining 3 weeks until the intervention ends. The means by which daily step count is achieved is up to the participant (i.e. planned walk or increased habitual walking activity). Participants will be able to view live on their smart watch or via Garmin Connect app, how many steps they have taken at any time to help them meet their daily step target. Intensity minutes target goal: Intensity minutes are earned based on a participant's current heart rate when compared to their average resting heart rate. Intensity minutes are earned once increased activity is detected by the smart watch. Participant's age, weight, height, and resting heart rate calculated by the Garmin device also factor into intensity minutes. Participants will attempt to increase their weekly intensity minutes score by 10% each week from baseline, until an increase of 50% is achieved at week 5. This volume will be then maintained or increased as tolerated for the remaining 3 weeks until the intervention ends. Strength training: Each home strength training session (3 per week) will start with a short warm up, i.e. 5-min walk to be followed by 6 stretching exercises targeting the lower limb, upper limb and spine. Once warmed up, participants will perform a circuit of 8 exercises with the help of the Physitrack app or hard-copy exercise program. It will involve large muscle groups in the following order (i.e. alternating arm and leg exercises to minimise muscle soreness and fatigue): 1. Lunges 2. Row 3. Sit to stand 4. Chest press 5. Hip abduction 6. Trunk rotation 7. Hip extension 8. Heel raise Sets and repetitions for each participant, along with training intensity (i.e., elastic band resistance) will be determined using pre-intervention assessment baseline data during the face-to-face meeting at the beginning of week 1. The modified Borg rating of perceived exertion scale (1 to 10) will be used where a score of 6 (i.e. able to speak 3 to 5 words comfortably) being the starting level. Once a score of 5 (i.e. able to speak more than 5 words comfortably) or less is perceived, the band resistance will be raised to the next level. The circuit of 8 exercises will consist of 1 to 3 rounds of single sets (10 to 20 repetitions) to allow full muscle group recovery in between. The speed of repetitions will focus on having a controlled concentric/eccentric portion of the movement. The training volume (sets x reps x band resistance) will be increased by 10% per week for 5 weeks and then maintained or increased as tolerated for a further 3 weeks. The volume targets will be emailed to participants weekly through the Physitrack app. Targets will also be discussed at the weekly telehealth session. Participants will complete a supplied daily exercise diary for monitoring of adherence to the prescribed exercise program. Telehealth coaching sessions Eight, weekly telehealth meetings will take place at a time that is suitable for the study participant, starting week 1 and continue through to week 8 of the study. Each session will last 10 to 20 minutes via phone using the Physi app or through an email link to a home computer. The aim of each meeting will be to monitor participant progress and troubleshoot any barriers or unforeseen difficulties that may arise across the week to maintain motivation for exercise. Health coaching strategies will be used such as: - use of a health coaching log form - setting clear goals - establishing a trusting relationship - using active listening and questioning techniques - providing constructive feedback - support to encourage independence in exercising - adaptability and flexibility to tailor the session to meet the needs and preferences of each individual participant In instances where technical difficulties prevent a participant from being able to log in to a telehealth session it may still be conducted over the phone. Physitrack health coaching email messages Physitrack is an exercise prescription app which allows remote contact between therapist's and their patients. Participants will need to download the Physitrack app onto their phones to be able to receive weekly emails and participate in weekly telehealth meetings. Personalised emails will be sent from Physitrack to participants at the beginning of each week and consist of encouraging messages and reminders of the benefits of exercise. They will also include fully narrated exercise videos so participants will have a clear understanding of their exercise program and goals each week. They will be scheduled to be sent to the participant's email each Monday morning between weeks 2 and 8 of the study. In the case of week 1, the email will be sent after the activity data has been downloaded and reviewed by the investigator at the week 1 start of intervention meeting that will occur in-person. Activity monitoring All participants will have their activity monitored 24 hours a day, 7 days a week (excluding showering and device recharging) for 8 weeks using a smart watch (Garmin). The smart watch will record activity during and outside of the personalised home exercise program. Participants will be provided with the smart watch at the conclusion of the pre-intervention meeting (week 0), to wear for one week to determine baseline activity levels. This data will be downloaded at the study visits at the beginning of week 1 (start of intervention meeting) and post-intervention assessment at the beginning of week 9. Participants will download the Garmin Connect app onto their smartphone and transfer data daily to avoid any potential loss of information. The metrics downloaded will include: - Steps taken per day - Average heart rate - Intensity minutes - Hours of sleep per day A brief (5 minute) training session will be held at the end of the pre-intervention visit to teach the participants how to wear, charge, and operate the smart watch. A more detailed training session will be held at the week 1 start-intervention visit to NeuRA. Participants will be taught how to use the smart watch and Garmin Connect app to self-monitor their daily activity levels and work toward meeting their daily and weekly activity goals. STUDY GROUPS Single group pre-post feasibility study. Participants will be those with a primary diagnosis of PMD who attend the PMD clinic at Neuroscience Research Australia (NeuRA). Participants will attend 3 study appointments at the following time points: - Pre-intervention - week 0, for initial assessment of baseline objective and subjective measures, provision of a smart watch (Garmin), education on its use and downloading of the Garmin Connect app onto participants phones. The watch is worn continuously for 1 week before returning for the next face to face meeting where baseline activity data will be downloaded for review. - Start-intervention - beginning of week 1, for downloading of 1 week of pre-intervention activity data to set exercise targets. Education on performing the prescribed home exercise program including use of supplied equipment (smart watch, elastic bands & exercise diary). The home exercise program will be provided both electronically using the Physitrack app downloaded onto participants phones and in hard copy via an exercise diary for participants to fill in as required. - Post-intervention - beginning of week 9, for reassessment of measures conducted at the pre-intervention assessment week 0. Downloading of 8 weeks of participant activity data from their Garmin Connect app. Gain feedback on program acceptability from participants via questionnaires which will contain questions regarding the home exercise experience, smart watch, telehealth and Physitrack use. NUMBER OF PARTICIPANTS This study will recruit 10 participants with a PMD over a 5-month period. NUMBER OF CENTRES - This study will be conducted at a single site, NeuRA, Randwick, NSW. - This study will be completed over a 1-year period: 5-months recruitment, a 5-month trial period and 2-months to analyse and report the results. The expected start date is July 2024.

Evaluation of BTV100 in Subjects With Dry Eye Disease

At the screening visit/Visit 1 (Day 1 minus 14 days), subjects who are eligible according to the inclusion and exclusion criteria will begin a 14-day run-in period during which they will self-administer 1 drop of single-masked vehicle to each eye twice daily (BID), morning and evening (at least 6-hour interval). At the time of the screening visit/Visit 1, subjects will be instructed to discontinue all over the counter (OTC) and prescription topical ophthalmic medications except for the vehicle or study drug throughout the study. At Baseline/Visit 2 (Day 1), subjects who continue fulfilling inclusion/exclusion criteria will be randomized to study drug or vehicle. Approximately120 subjects will be randomized. Subjects will be randomized to one of the following 4 treatment groups. Following randomization, subjects being masked to treatment assignments will be instructed to self-administer 1 drop of investigational product (IP) into each eye twice daily, morning and evening (at least 6-hour interval). Subjects will be instructed to return to the clinic to be evaluated at Day 15 (Visit 3), Day 29 (Visit 4), Day 57 (Visit 5), and Day 85 (Visit 6).

End-Tidal Oxygen for Intubation in the Emergency Department

BACKGROUND AND INTRODUCTION Rapid Sequence Intubation (RSI) is a common procedure in Emergency Departments (ED). However, it is a high-risk procedure and is associated with significant complications including hypoxia, failed intubation, hypotension, trauma and aspiration. (1-3) Specifically, hypoxia during intubation can lead to poor outcomes such as dysrhythmias, haemodynamic compromise, hypoxic brain injury and death and therefore oxygen desaturation is of primary concern during any intubation procedure. (4, 5) In order to prevent desaturation events during intubation, a number of steps are taken by clinicians. These include optimal patient positioning, adequate preoxygenation, assessment of airway anatomy and development of a detailed airway plan as well as the use of apnoeic oxygenation.(6) Effective preoxygenation is vital to ensure that the patient does not develop hypoxia during the period between induction (administration of sedative and paralytic agents) and restoration of ventilation by successful endotracheal intubation or rescue breathing. Various methods of preoxygenation have been developed to wash the nitrogen out of the lungs (denitrogenation) which allows the functional residual capacity (FRC) to act as an oxygen reservoir during intubation, which prolongs safe apnoea time, therefore, preventing desaturation whilst an endotracheal tube (ETT) is placed. Adequate preoxygenation is especially important for those patients at highest risk of hypoxia during the RSI. This patient group includes those with underlying lung pathology e.g. pneumonia, patients with increased metabolic demand e.g. sepsis, patients with an oxygen requirement prior to RSI, or patients with underlying conditions that predisposes to hypoxia e.g. obesity. For many years anaesthetists have used end-tidal oxygen (ETO2) levels to guide the effectiveness of preoxygenation. ETO2 measures the exhaled oxygen concentration and is a marker of the oxygen concentration in the alveoli. Prior to induction, anaesthetists most commonly preoxygenate with a face-mask seal via either a circle circuit, Mapleson circuit, or bag valve mask. ETO2 provides an objective measurement of preoxygenation efficacy. The Difficult Airway Society guidelines suggest aiming for an ETO2 of ≥87% prior to commencing RSI.(7) ETO2 levels are not routinely measured in Emergency Departments. Currently, it is not possible to measure the effectiveness of preoxygenation in the ED. Pulse-wave oximetry reflects peripheral oxygen saturation and not the pulmonary oxygen concentration. Therefore, to attempt to optimize preoxygenation the emergency clinician currently can only use time as a surrogate. The typically recommended duration of preoxygenation is > 3 minutes. Recently, the investigators conducted two multi-site studies (Ethics identifier: 2019/ETH06644) that investigated the use of ETO2 in the ED.(8, 9) The first study was conducted with clinicians blinded to the ETO2 result (8). The investigators demonstrated that preoxygenation was uniformly poor with only 26% of patients achieving the required target ETO2 of ≥85%. The investigators then completed a second study where clinicians had access to ETO2 values and found that the proportion of patients reaching levels ≥85% was improved to 67% of patients. (9) The prevalence of hypoxemia (SpO2 <90%) in the group blinded to ETO2 was 18% (n=18, 95% CI: 11% to 27%) and was 8% in the group where ETO2 was available (n = 8, 95% CI: 4% to 15%). These studies indicate that the use of ETO2 may substantially improve preoxygenation in the ED and therefore reduce the risk of hypoxia. These studies, however, were focused on preoxygenation practices and not patient-oriented outcomes (hypoxia) and were limited in design and resources. Consequently, it is still unclear whether the use of ETO2 in the ED leads to improved clinical outcomes. RATIONALE FOR PERFORMING THE STUDY The aim of this study is to determine the effectiveness of ETO2 monitoring in preventing desaturation for patients with a high risk of hypoxia undergoing RSI in ED. HYPOTHESIS The investigators hypothesise that the use of ETO2 monitoring leads to reduced rates of oxygen desaturation during the peri-intubation period compared to when it is not used.

A Phase I Study of CS2009 in Participants With Advanced Solid Tumors

A Study to Evaluate the Efficacy and Safety of Orally Administered VX-01

This is a Phase 2, multi-center, double-masked, randomized, placebo-controlled, parallel group study to evaluate the efficacy of oral doses of VX-01 in subjects with moderate to severe NPDR, without CI-DME. Approximately 100 male and female subjects aged ≥ 18 years with a documented diagnosis of Type 1 Diabetic Mellitus or Type 2 Diabetic Mellitus with moderate to severe NPDR (without CI-DME) will be enrolled, if they meet all the eligibility criteria for the study. Subjects will be randomized 1:1 to 1 of 2 study cohorts: - Cohort 1 (n = 50): VX-01 (film-coated tablets, 150 mg administered BID) - Cohort 2 (n = 50): Placebo (film-coated tablets, administered BID) Subjects will be stratified by the presence or absence of proliferative diabetic retinopathy (PDR) and by glycated hemoglobin (HbA1c) of ≥ 8.5% or < 8.5% at Screening. All subjects will take 1 tablet of VX-01 or placebo BID for 52 consecutive weeks. All subjects will be followed for 12 weeks after completion of treatment at Week 52. The Sponsor, study site staff, monitors, personnel, and subjects will be masked to treatment assignment during the entirety of the study.