Guanajuato, Leon, Mexico

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

Study to Investigate Comparative Efficacy, Safety and Immunogenicity Between AVT16 and Entyvio

The study will consist of a screening period, a treatment and assessment period and an End of Study visit. Eligibility for the study will be determined during a screening period. Subjects who meet the eligibility criteria will be randomised to either AVT16 or Entyvio.

A Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Multiple Sclerosis.

Participants with relapsing MS from the Phase 2b LTS16004 parent study will continue open-label (OL) tolebrutinib. All participants from the Phase 3 parent studies (EFC16033, EFC16034, EFC16645, and EFC16035) will learn which treatment they received in the parent study: - If from one of the Phase 3 relapsing MS studies and on teriflunomide, an accelerated elimination procedure or a 3-month washout period is required prior to starting OL tolebrutinib. If on teriflunomide, and benefiting and recommended by the Investigator, the participant may opt to continue teriflunomide outside of the LTS17043 study, if clinically appropriate. If on tolebrutinib, the participant will continue tolebrutinib. - All participants from one of the Phase 3 progressive MS studies will start OL tolebrutinib. - If a participant already started OL tolebrutinib in the Phase 3 parent study this will be continued. - RMS participants who are not eligible for OL tolebrutinib per Health Authority and/or ethics committee decisions on the study conduct (ie, partial hold on initiation of tolebrutinib) will continue their parent study treatment assignment as per their randomization from the parent study. The treatment duration per participant will be approximately 3 years of OL tolebrutinib.

A Study to Assess the Effect of Dexpramipexole in Adolescents and Adults With Severe Eosinophilic Asthma.

This is a multicenter, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and safety of dexpramipexole in adults and adolescents with severe, inadequately controlled asthma with eosinophilic phenotype on medium to high-dose inhaled corticosteroids (ICS )and at least one additional asthma controller medication with or without oral corticosteroids (OCS). Approximately 1400 participants will be randomized globally. Participants will receive dexpramipexole, or placebo, administered orally, over a 52-week treatment period. The study also includes a post-treatment follow-up period of 4 weeks.

The NEU-STIM Trial

Rationale: A randomised study demonstrated that preterm infants who received repetitive stimulation at birth (10 second episodes of stroking of the soles of the feet and/or back, followed by 10 seconds rest) showed an increase in respiratory effort. This may in turn improve clinical outcomes as improved breathing effort may reduce the need for invasive respiratory support. Tactile stimulation can be immediately and easily performed at birth at no extra cost. It therefore has great potential to be implemented in delivery rooms (DRs) worldwide. Objective: To determine the effect of repetitive tactile stimulation compared to selective stimulation on oxygenation of the infant at 5 minutes after birth. Study design: This is a stepped-wedge cluster randomised controlled trial. The participating centre, rather than the individual infant, will be the unit of randomisation. This design is appropriate to test the effect of an intervention that encompasses a behavioral aspect - in this case the performance of tactile stimulation. Study population: Infants born before 32 weeks of gestation will be included in this trial. Intervention: At the start of the study, each participating centre will perform selective tactile stimulation in accordance with international guidelines, as is their usual practice. Clinicians will gently rub the back, chest, extremities or soles of the feet if they consider the breathing of the infant to be insufficient or absent. In the second stage of the study, centres will be randomised to switch their stimulation approach to repetitive stimulation. Clinicians will then gently rub the back, chest, extremities or soles of the feet for 10 seconds. To avoid extinction of the stimulatory effect (reflex), every 10 second period of stimulation will be followed by 10 seconds of rest (no stimulation). Repetitive stimulation will be performed for the first 5 minutes of life, or longer if the breathing is still considered insufficient or absent. Main study parameter: The proportion of infants with pre-ductal oxygen saturation (SpO2) ≥ 80%.

Study to Evaluate the Efficacy, Safety, and Tolerability of IMU-838 in Patients With Relapsing Multiple Sclerosis

This study will be a multicenter, randomized, double-blind, placebo-controlled study with a blinded Main Treatment Period (MT) and an Open Label Period (OLE) to evaluate the efficacy, safety, and tolerability of IMU-838 in adult patients with RMS. The study will consist of the following periods: Screening Period: Approximately 28 days Main Treatment Period: Up to 72 weeks (approximately 15 months) Open Label Extension Period: Up to approximately 8 years

Study for Participants Continuing From Pfizer-sponsored Palbociclib (a Study Medicine) Studies

This is an open-label study to provide continued access to treatment for eligible participants who continue to derive clinical benefit as determined by the investigator from study intervention(s) in a Pfizer-sponsored palbociclib clinical study (Parent Study)

Human Anti-D (rh) Immunoglobulin (Rhesoglobin) Efficacy, Safety and Some Pharmacokinetics Parameters in Pregnant Women

The screening stage The pregnant woman (participant) has to sign an informed consent. After the signed informed consent procedure, the patient is assessed for meeting the inclusion and non-inclusion (exclusion) criteria. Patients who were included in the study are assessed according to additional criteria for inclusion in the "Pharmacokinetics" subgroup. The clinical stage According to the study protocol, patients receive two prophylactic doses of the study drug at a dose of 300 mcg - at 28 weeks of gestation and within 72 hours after delivery. Patients receive the second dose only in the case of the birth of an Rh-positive child. Before and after each injection of the drug, blood will be taken to control the level of anti-Rh0 (D) antibodies. In the "Pharmacokinetics" subgroup, additional blood samples will be taken to determine the following pharmacokinetic parameters: - Serum clearance - Volume of distribution - AUC (area under curve) - Т1/2 (α and β) (half-life time) - Cmax (maximum/peak serum concentration) - Tmax (time to reach the maximum serum concentration) - Kel (elimination rate constant) The final stage The patient should be monitored for 6 months ± 5 days, after the last injection of the drug, blood samples are taken after 3 and 6 months to assess sensitization to the Rh antigen.

A Phase 3 Study to Investigate the Efficacy and Safety of SHR0302 With Moderately to Severely Active Ulcerative Colitis

This study consists of a screening period followed by a placebo-controlled Part 1 phase and then a placebo-controlled Part 2 phase. An open label Part 3 phase is open to subjects who: complete the Part 2, are considered non-responders following the Part 1, or have disease worsening during Part 2.

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