The PhINEST Study - Pharyngeal ICU Novel Electrical Stimulation Therapy

Study Overview
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Brief Summary
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This is a prospective, multi-site, randomised, sham-controlled, single-blind (outcome assessor-blinded) study designed to assess the effects of Pharyngeal Electrical Stimulation (PES) (using Phagenyx®) for the treatment of oropharyngeal dysphagia after invasive mechanical ventilation (of any duration) by means of naso or oro-tracheal tube in critically ill intensive care unit (ICU) patients.

Detailed Description
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The PhINEST study is designed to assess the effects of Pharyngeal Electrical Stimulation (PES) (using Phagenyx®) for treatment of oropharyngeal dysphagia after invasive mechanical ventilation (of any duration) by means of naso or oro-tracheal tube in critically ill intensive care unit (ICU) patients. The main clinical outcomes assessing unsafe swallows and dysphagia severity will be measured using the gold standard, i.e. Fiberoptic Endoscopic Evaluation of Swallowing (FEES) and bedside swallowing assessments on day 2* after completion of final PES treatment. Randomisation will be on a 1:1 basis at each site stratified for neurological vs. non-neurological reason for admission (Acute Physiology and Chronic Health Evaluation (APACHE) IV diagnostic group). Patients will receive either PES/sham treatment in addition to standard supportive ICU care and standard of care treatments for dysphagia. Administration of all protocol-specific assessments will be conducted by personnel blinded to treatment assignment. The study will follow an adaptive population enrichment and sample size re-estimation (SSR) design with one interim look. The study will start with a planned sample size of 200 patients and a maximum (evaluable) sample size of 360. Interim analysis after completion of approximately 140 (evaluable) patients will determine: I. futility stopping; OR II. sample size increase for the overall sampled population; OR III. Enrichment based on the composite primary endpoint by pre-defined subgroups (neurological vs. non-neurological reason for admission according to APACHE IV diagnostic groups). Thus enrollment of patients in the non-performing sub-group will be stopped at the interim while a sample-size re-estimation based on conditional power will be carried out for the other sub-group. All interim decisions will be based on conditional power which for the Finkelstein-Schoenfeld (FS)-statistic will need to be computed via Monte-Carlo simulations. Up to thirty (30) investigational sites across Europe are planned to participate in this study which is expected to last 48 months from first patient first visit to last patient last visit. Patients will be assessed at the following intervals: screening, baseline, on day 2* after completion of final study treatment, 7 ± 1 days after final study treatment and 14 ± 1 days after final study treatment (or hospital discharge if earlier). 30-day and 90-day mortality data will also be collected from the patients medical notes/electronic heath records/telephone call (no additional visit required). *The day two (FU1) visit is to be conducted on the second day ( 24hrs) following final PES treatment but may, under certain circumstances, be conducted upon/by the fourth day ( 60 hrs) following final study treatment in instances where the final study treatment is delivered on late Friday and where FEES assessment is only possible early on Monday as no weekend FEES service is available at the investigation site.

Official Title
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The PhINEST Study - Pharyngeal ICU Novel Electrical Stimulation Therapy: a Prospective, Multi-site, Randomised, Sham-controlled, Single-blind (Outcome Assessor-blinded) Study.

Conditions
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Dysphagia

Intervention / Treatment
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* Device: Pharyngeal Electrical Stimulation (PES)


Participation Criteria
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Eligibility Criteria
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Pre-screening Inclusion Criteria: All of the following criteria must be met for inclusion: Age ≥ 18 ≤ 85, Emergency ICU admission (unplanned admission), Recent extubation following invasive mechanical ventilation (of any length of time) by means of endotracheal tube, Presence of post-extubation dysphagia as determined by the participating Sites' Standard Of Care (SOC). Screening / Enrolment Criteria: To be eligible for enrolment in this study, an individual must meet all of the following additional criteria: Presence of written informed consent according to respective national guidelines, Dysphagia severity status classified according to PAS on FEES assessment as 'aspiration' (PAS score ≥ 6), Richmond Agitation and Sedation Scale (RASS) score within the range of -1 to +2 (i.e. if score equals -2, -3, -4 or +3, +4, patient is excluded). Randomisation Inclusion Criteria (post-consent) The following additional criteria must be met for randomisation: • Successful placement and subjective tolerance of the Phagenyx® Catheter within 2 days of extubation.(post consent) Exclusion Criteria: An individual who meets any of the following criteria will be excluded from enrolment in this study: Nasal anatomical deformity, nasal airway obstruction; patient who have had recent oral, nasal or oesophageal surgery or patient presenting with facial and/or cranial fractures or any other circumstance (e.g. history of oesophageal perforation, stricture, pouch, resection or rupture) where the placement of a standard nasogastric feeding tube (NGT) would be deemed unsafe, Cardiac or respiratory condition that might render the insertion (placement) of a catheter into the throat unsafe, Permanently implanted electrical devices, Are pregnant (pregnancy test) or known lactating women, Have non-neurogenic dysphagia (e.g. Cancer-related), Any prior tracheostomy, Patients who at the time of extubation have any treatment limitation (i.e., palliative care, life expectancy less than 48 hours, or are moribund), that prevents or would prevent compliance with study-specific instructions or procedures (as judged by the investigator), Severe cognitive impairment or other reasons that prevents compliance with study-specific instructions or procedures (as judged by the investigator), Previous history of dysphagia of any origin, Pre-existing tube feeding of any form (e.g. percutaneous gastric/enteral feeding tube related to previous injuries indicating previous dysphagia. NGTs are not an exclusion criterion), Participation in another interventional study (medicinal or device) that could influence the outcomes of PES, Treatment of dysphagia with other forms of electrical stimulation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active PES<br>Patients randomized to receive active Pharyngeal Electrical Stimulation (PES) via a Phagenyx Catheter. | Device: Pharyngeal Electrical Stimulation (PES)<br>* The Phagenyx® system is a two-part neurostimulation system. It is composed of a durable component called the Base Station and the single-use sterile disposable Catheter. The Base Station acts as the user interface and provides the means to generate, optimize and monitor the delivery of electrical stimulation to the oropharynx. The Phagenyx® devices are CE labelled (2012) and will be used in accordance with their intended use label.<br>* Other names: Phagenyx;|
| Sham Comparator: Sham PES<br>Patients randomized to sham will not receive any Pharyngeal Electrical Stimulation (PES) but will still have the Phagenyx Catheter inserted. | Device: Pharyngeal Electrical Stimulation (PES)<br>* The Phagenyx® system is a two-part neurostimulation system. It is composed of a durable component called the Base Station and the single-use sterile disposable Catheter. The Base Station acts as the user interface and provides the means to generate, optimize and monitor the delivery of electrical stimulation to the oropharynx. The Phagenyx® devices are CE labelled (2012) and will be used in accordance with their intended use label.<br>* Other names: Phagenyx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness of Phagenyx® treatment in reducing severity of unsafe swallows - Penetration-Aspiration Scale (PAS) Scores | Analysis of a two endpoints composite (FS-statistic) on a hierarchy of clinical priorities: Endpoint 1 - Swallowing safety based on worst PAS score in up to 4 thin (water) boli for each patient during FEES assessment converted to a trichotomised ordinal response of safe (PAS 1-3), penetration (PAS 4-5), or aspiration (PAS 6-8). The PAS provides a scoring system for airway closure and clearance during FEES. The PAS is a validated 8-point scale quantifying penetration and aspiration events primarily by the depth to which material passes into the airway and whether or not it is ejected. | Day 2 ( 24 to  60 hours) after the final Phagenyx® treatment | 
| Effectiveness of Phagenyx® treatment in reducing the severity of unsafe swallows - Dysphagia Outcome and Severity Score (DOSS) score | Analysis of a two endpoints composite (FS-statistic) on a hierarchy of clinical priorities: Endpoint 2 - DOSS scale score determined by bedside assessment. The DOSS is a simple, easy-to-use, 7-point scale developed to systematically rate the functional severity of dysphagia based on objective assessment and make recommendations for diet level, independence level, and type of nutrition. Severe dysphagia Moderately severe dysphagia Moderate dysphagia Mild-moderate dysphagia Mild dysphagia Functional limitation and modified independence Normal in all situations | 7±1 days after the final Phagenyx® treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness of Phagenyx® treatment in improving DOSS score. | Changes in nutritional management and severity of dysphagia as measured by the DOSS score. | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment on time from to feeding tube removal. | Changes in nutritional management and severity of dysphagia as measured by time from randomisation to removal of feeding tube. | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment on time to oral intake. | Changes in nutritional management and severity of dysphagia as measured by time to oral intake (if applicable). | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment on total days of enteral feeding. | Changes in nutritional management and severity of dysphagia as measured by total days of enteral feeding. | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment in improving Functional Oral Intake Scale (FOIS) score. | Changes in nutritional management and severity of dysphagia as measured by the FOIS score. The FOIS provides a scoring system to document the functional level of oral intake of food and liquid in patients with dysphagia. It is a validated 7-point ordinal scale easily completed from information contained in medical charts, dietary journals, and/or patient reports. Nothing by mouth Tube dependent with minimal attempts of food or liquid Tube dependent with consistent intake of liquid or food Total oral diet of a single consistency Total oral diet with multiple consistencies but requiring special preparation or compensations Total oral diet with multiple consistencies without special preparation, but with specific food limitations Total oral diet with no restriction | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment in improving Dysphagia Severity Rating Scale (DSRS) score. | Changes in nutritional management and severity of dysphagia as measured by the DSRS score. The DSRS is a simple to use, validated 13-point scale composed of a 3-component score that includes feeding independence, but nutrition level and diet modification is split into the components of liquid feeding and overall diet consistency. The DSRS is the sum of the scores of each of the 3 individual components (range 0-4 for each component) rather than a combination of the three components into an ordinal scale. Best score = 0 (no dysphagia) Worst score = 12 (NPO) | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment on time from extubation to ICU discharge | General health outcome measured by time from extubation to ICU discharge (days). | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment on length of stay in ICU | General health outcome measured by length of stay in ICU (days). | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment on length of stay in hospital. | General health outcome measured by length of stay in hospital (days). | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment on number of patients with re-intubation during hospital stay | General health outcome measured by number of patients with re-intubation during hospital stay. | Up to 14 ± 1 days after the final Phagenyx® treatment (or hospital discharge if earlier). | 
| Effectiveness of Phagenyx® treatment on mortality | General health outcome measured by 30-day and 90-day mortality. | Up to 90 days after completion of the final Phagenyx® treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dysphagia, Extubation, Intensive Care Unit, Pharyngeal Electrical Stimulation, Oropharyngeal Dysphagia, Mechanical Ventilation, Critically ill patients, Post-Extubation Dysphagia