Resca, Com. Dobrosloveni, Romania

Efficacy and Safety of KBP-336 in Obese Individuals with Osteoarthritis

A Stepped Wedge Cluster Randomised Trial of Video Versus Direct Laryngoscopy for Intubation of Newborn Infants

INTRODUCTION Many newborn infants have difficulty breathing after birth. Some of these babies have a tube inserted into their "windpipe" (trachea) - an endotracheal tube (ETT) - through which they are given breathing support (ventilation). When clinicians attempt to intubate (insert an ETT), they use an instrument called a laryngoscope to view the airway in order to identify the entrance to the trachea (larynx). Standard laryngoscopes have a "blade" (which, despite its name, is not sharp) with a light at the tip. Doctors insert the blade into the baby's mouth to view the larynx. Traditionally, clinicians used a standard laryngoscope to look directly into the baby's mouth to view the larynx (direct laryngoscopy, DL). When clinicians attempt to intubate newborns with DL, less than half of first attempts are successful. Also adverse effects - such as falls in the blood oxygen levels (fall in oxygen saturation (SpO2), or "desaturation"), slowing down of the heart rate (bradycardia), oral trauma - are relatively common. In recent years, video laryngoscopes (VL) have been developed. In addition to a light, VL have a video camera at the tip of the blade. This camera acquires a view of the larynx and displays it on a screen that the clinician views when attempting intubation (indirect laryngoscopy). In a randomised study performed at the National Maternity Hospital, Dublin, Ireland, more infants were successfully intubated at the first attempt when clinicians used VL compared to DL [79/107 (74%) versus 48/107 (45%), P<0.001]. While this study was large enough to show that VL resulted infants being successfully intubated at the first attempt in one hospital, it couldn't give information about how it might work in a range of hospitals, and it wasn't large enough to see what effect VL had on adverse events. There is a large difference in cost between a standard laryngoscope (approx. €300) and a video laryngoscope (approx. €21,000). This is a matter of concern for all hospitals, particularly in settings where resources are more limited. The investigators aim to assess whether VL compared to DL results in more infants being intubated at the first attempt without physiological instability. STUDY DESIGN A recent single centre study reported that that more newborn infants were successfully intubated at the first attempt when VL was used to indirectly view the airway compared to DL. This study was not large enough to determine the effect of VL on adverse effects that are seen commonly (e.g. desaturation) or more rarely (e.g. bradycardia, receipt of chest compressions or adrenaline, oral trauma) during intubation attempts. For the current study, the investigators chose a stepped-wedge cluster randomised controlled design, where the participating centre, rather than the individual infant, will be the unit of randomisation. This design has been found appropriate to test the effects of an intervention that encompasses a behavioural aspect and to implement interventions while studying them at the same time. In this study, all centres will begin in the "control group"; where clinicians will routinely attempt intubation with DL, as is their usual practice. At specified intervals, centres will be randomly assigned to cross over to the "intervention group", where clinicians will routinely attempt intubation with VL. All participating centers will have included patients in both arms by the end of the study. SAMPLE SIZE ESTIMATION To determine the intra-cluster correlation (that means the correlation between two observations from the same centre), the investigators used the dataset of the MONITOR trial that included infants from 7 delivery rooms worldwide. In this trial, the intra-cluster correlation for intubation in the delivery room was reported as 0.1. This complete stepped-wedge cluster-randomized design includes 21 time periods (including the baseline) and 20 centres that will be including patients, with each randomised to a unique sequence. Each time period lasts a fortnight. Each time period, 1 centre will switch their treatment from DL to VL. With all centres including 2 patients each time period, 42 patients will be included per centre which will provide a total sample size of 840 patients. Assuming a control proportion of 0.4, this sample will achieve 90% power (0.9091) to detect a treatment proportion of 0.55, assuming a conservative ICC of 0.05. The power is not very sensitive to ICC values up to 0.1 (power of >90% to detect difference 40% versus 56%). The test statistic used is the two-sided Wald Z-Test. TREATMENT OF SUBJECTS DIRECT LARYNGOSCOPY (DL, control period) At the start of the study, clinicians at participating centres will attempt intubation using a standard laryngoscope to perform DL as is their normal practice. VIDEO LARYNGOSCOPY (VL, intervention period) For each centre, a lot will be drawn which indicates the month in which endotracheal intubation will be routinely attempted with VL rather than DL. In the month before the switch, centres will be provided with a C-MAC VL by the manufacturers, Karl Storz-Endoskop (Tuttlingen, Germany). The system will be provided on loan for the duration of the study and will consist of an 8" high-definition monitor with connecting cable and reusable straight Miller type blades size 0 and size 1. The equipment will be demonstrated by representatives from Karl Storz, and clinicians who intubate babies at participating hospitals will be encouraged to practice with the equipment on mannequins. We will have an virtual meeting with each centre in the week before they are due to switch to review the protocol, data collection and to answer any queries that they may have. All other procedures in the delivery room and NICU will be performed according to international and local guidelines. All other aspects of the approach to intubation at the participating centre are at the discretion of the local clinicians and should remain the same for the duration of the study; e.g.: - The drugs used before intubation attempts (e.g. opiate, atropine, curare-like drug) - The route by which intubation is usually attempted (i.e. oral or nasal) - Whether they use a stylet is routinely used - Whether supplemental oxygen is given during attempts

A Prospective Observational Study of Video Laryngoscopy Versus Direct Laryngoscopy for Insertion of a Thin Endotracheal Catheter for Surfactant Administration in Newborn Infants

Many newborn infants have breathing difficulty after birth, particularly when they are born prematurely. Many of these infants are supported with nasal continuous positive airway pressure (NCPAP). Some of the infants deteriorate despite treatment with NCPAP and have a thin catheter inserted into their trachea for the administration of surfactant, which is then immediately removed (often referred to as "less-invasive surfactant administration" or LISA). Insertion of a thin catheter is usually performed by doctors who are experienced at intubation (i.e. inserting endotracheal tubes, ETTs). They look directly into the the infants mouth using a standard laryngoscope to identify the opening of the airway (i.e. perform direct laryngoscopy). More recently video laryngoscopes have been developed. These devices display a magnified image of the airway on a screen that can be viewed indirectly by the doctor attempting to insert the ETT or thin catheter, and also by others. A single centre study reported that more infants were successfully intubated at the first attempt when doctors performed indirect video laryngoscopy compared to direct laryngoscopy. It is possible to independently verify when a doctor has correctly inserted and ETT, for example by detecting carbon dioxide coming out of the tube or seeing condensation in the tube during exhalation, or by hearing breath sounds by listening to the chest during positive pressure inflations. It is not possible to independently verify whether a doctor has correctly inserted a thin catheter under direct laryngoscopy, by these or other means. The standard (and to date only) way of confirming that a thin catheter has been correctly inserted is to rely on the report of the operator. Video laryngoscopy, in contrast, allows the independent verification of the tip of a thin catheter by one or more people observing the screen. The investigators are performing NEU-VODE, a stepped wedge cluster randomised study of the introduction of video laryngoscopy versus direct laryngoscopy for the intubation of newborn infants. Alongside this study, the investigators are performing a study of infants who have a thin endotracheal catheter inserted under video laryngoscopy versus direct laryngoscopy. As it is not possible to measure the outcome of successful insertion of the thin catheter equally in both groups, this is a prospective observational cohort study. The investigators will record information on infants who have a thin catheter inserted into the trachea for the purpose of surfactant administration at centres participating in the NEU-VODE study. The type of laryngoscope used for thin catheter insertion attempts will not be mandated; instead, the investigators will compare the information of groups within the cohort who have their first attempt made using the video laryngoscope to the group who have their first attempt made with direct laryngoscopy.

Prevention of CIPN Using Compressive Therapy

Cardiopulmonary Exercise Testing in Cardiosurgery Patients

Rhu-pGSN for Acute Respiratory Distress Syndrome (ARDS)

Potential subjects hospitalized with pneumonia or other infections are to be screened within 24 hours of diagnosis of ARDS. The Sponsor aims to identify as early as possible patients in the hospital who have developed acute hypoxemic respiratory failure within 7 days of the precipitating infection (often fever, rigors, chills, increased heart rate, increased respiratory rate, pain, cough, etc.) leading to ARDS resulting in mechanical or noninvasive ventilation or high-flow nasal oxygen (HFNO) supplementation with ≥50% O2 at a flow rate of ≥30 L/min. Patients who do not qualify for the study at the initial screening visit because of mild ARDS may subsequently progress to moderate-to-severe ARDS and should be reassessed at least daily for the 7 days following the precipitating infection. Once informed consent is obtained, the following assessments/procedures will be performed: 1. Confirm the potential participant has acute hypoxemic respiratory failure qualifying as moderate-to-severe ARDS for ≤48 hours following a suspected or confirmed infection within the preceding week. Moderate-to-severe ARDS is defined by the calculated or estimated ratio of arterial pressure of O2 to the fraction of inspired O2 [P/F ratio] ≤150. The P/F ratio will be computed from the most recent arterial blood gas obtained no more than 12 hours earlier than randomization. For potential subjects on high-flow nasal oxygen with ≥50% O2 at a flow rate of ≥30 L/min, the P/F ratio will be estimated assuming 50% delivered O2. If eligible and entered in the trial, the following steps should be taken. 2. Record medical history, including concomitant medications and current clinical status. Specify the site and etiology (if known) of infection, indicating if the lung ("direct ARDS") or another organ ("indirect ARDS") is the primary site of infection. 3. Perform pregnancy test (urine or blood) for women of childbearing potential if not already performed during the current hospitalization. 4. Collect pretreatment blood samples for measurement of baseline pGSN and analysis of antibodies against pGSN. 5. Perform physical examination and document results of the chest x-ray (CXR) and/or computed tomography (CT) scan, if CXR is inadequate if not already available as per SOC. 6. Obtain blood and sputum cultures and electrocardiogram (EKG) per SOC (if not already performed). Document the site of infection by collecting specimens as indicated: sputum (bacterial, viral, and mycobacterial, as indicated) and blood cultures, sputum Gram-stains, antigen detection on respiratory and urine specimens, and syndromic nucleic acid amplification tests (NAATs) on respiratory specimens (including a viral and other respiratory pathogen polymerase chain reaction [PCR] panel), where possible. Other specimens from possible sites of infection (e.g., urine, intra-abdominal drainage, skin or soft-tissue abscesses) should be cultured when available. 7. Measure routine lab tests at local (hospital) laboratory per local custom/SOC collect aliquots f- blood for subsequent biomarker assays (including, but not limited to C-reactive protein [CRP], procalcitonin, interleukin [IL]1β, IL6, IL10, and tumor necrosis factor [TNF]) for analysis at the central laboratory. 8. If eligibility criteria are satisfied, the subject will be randomized 1:1 (rhu-pGSN:placebo) by site to a treatment group and treated within 12 hours of randomization and no later than 48 hours after the diagnosis of moderate-to-severe ARDS. Randomized subjects will receive the assigned dose of rhu-pGSN or an equal volume of visibly indistinguishable sterile saline placebo as soon as possible but beginning no later than 48 hours after the diagnosis of moderate-to-severe ARDS. After reconstitution, rhu-pGSN is not to be kept at room temperature for >2 hours prior to beginning study drug administration. A single loading dose of rhu-pGSN at 24 mg/kg followed by 5 daily doses of rhu-pGSN at 12 mg/kg of measured or estimated actual body weight starting 24 hours after the loading dose or an equal volume of indistinguishable saline placebo will be administered. A window of ±2 hours will be allowed around dosing times. Study drug is administered by an IV push through a 0.2 μm filter. The syringe, filter, and extension tubing for administration of study drug are to be connected as close to the subjects as possible. The primary efficacy endpoint of all-cause mortality will be assessed at Day 28. All-cause mortality will also be assessed on Days 7 and 14. Discharged subjects will undergo follow-up evaluation on Days 14 and 28, preferably but not necessarily in person. Survival at Day 60 will be confirmed by telephonic contact or after 3 failed attempts, review of hospital and public records that document survival or death. Screening laboratory and other tests may be used as baseline values and do not need to be repeated if performed within 24 hours prior to randomization unless otherwise dictated by SOC. However, the blood sample for analysis of pGSN levels is to be repeated if not collected within 15 minutes before initiating the first dose of study drug. Repeat CXRs and/or CT scans and labs/cultures are to be obtained during the hospitalization if/when indicated by SOC. On Days 1 (predose) and 28, blood samples for analysis of antibodies against pGSN are to be collected, if possible. Repeat blood and other cultures should be obtained per SOC. An independent Data and Safety Monitoring Board (DSMB) consisting of at least 2 physicians and 1 statistician with appropriate scientific and medical expertise will be formed, and its roles and responsibilities will be described in the DSMB charter. The DSMB will perform 5 periodic reviews of safety data emphasizing deaths and SAEs and will monitor stopping rules to pause enrollment. There will be no pause on enrollment during the planned unblinded periodic reviews. These reviews will be performed after the first 50, 100, 200, 300, and 400 subjects in the Safety Analysis Set have either completed 28 days of follow-up, have died, or have discontinued from the study prior to completing 28 days of follow-up. DSMB members will be provided with unblinded data. Based on the results of each of the planned periodic reviews, the study will be paused only if there is a relative increase of 25 percentage points in the incidence of death or SAEs in the rhu-pGSN treatment group compared to the placebo group. A futility analysis will be performed at the 300-subject review. The Sponsor will take appropriate action based on the recommendation of the DSMB. The DSMB will also review expedited reports of any SAEs throughout the study and may request additional looks at safety data at their discretion. Enrollment will continue during all safety analyses unless otherwise recommended by the DSMB chair.

Evaluate Efficacy, Safety and Tolerability of JTT-861 in Subjects With Heart Failure With Reduced Ejection Fraction

A Study to Assess the Effect of Dexpramipexole in Adolescents and Adults With Severe Eosinophilic Asthma (EXHALE-3)

Antiangiogenic Therapy for Children with Recurrent Medulloblastoma, Ependymoma and ATRT

A Phase 2 Study to Evaluate MORF-057 in Adults With Moderately to Severely Active Crohn's Disease

This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of induction therapy with 2 active dose regimens of MORF-057 versus matching placebo in adult study participants with moderately to severely active CD. After completion of the 14-week Induction Period, all participants will receive open-label MORF-057 during the 38-week Maintenance Period. All participants who complete the full 52-week Treatment Period will also have the opportunity to continue treatment in a 52-week Maintenance Extension.