PROSpect: Prone and Oscillation Pediatric Clinical Trial

• ClinicalTrials.gov Identifier: NCT03896763
• Recruitment Status: Enrolling by invitation
• First Posted: April 1, 2019
• Last Update Posted: September 1, 2022
• Sponsor: University of Pennsylvania
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University Medical Center Groningen; Boston Children's Hospital; University Hospitals Cleveland Medical Center
• Information provided by (Responsible Party): Martha A.Q. Curley, PhD, RN, University of Pennsylvania

Tracking Information

• First Submitted Date: October 22, 2018
• First Posted Date: April 1, 2019
• Last Update Posted Date: September 1, 2022
• Actual Study Start Date: May 1, 2019
• Estimated Primary Completion Date: January 1, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 27, 2019)

Ventilator-free Days (VFD) [ Time Frame: 28 days ]

Our primary research hypothesis is that children with severe PARDS randomized to either prone positioning or HFOV will demonstrate more ventilator-free days. We hypothesize that a superior treatment would improve VFD by at least 2 days, a clinically meaningful difference. VFD is the number of days within 28 days that a patient is alive and free of mechanical ventilation. Improvement in VFD will be considered within the context of patient safety; specifically, patients must also exhibit a similar safety profile.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 27, 2019)

Nonpulmonary organ failure-free days (OFFD) [ Time Frame: 28 days ]

Our secondary research hypothesis is that children with severe PARDS randomized to either prone positioning or HFOV will demonstrate more more nonpulmonary organ failure-free days. OFFD is the number of days within 28 days that a patient is alive and free of clinically significant non-pulmonary organ failure. Nonpulmonary organ failure-free days will be calculated based on the clinically important nonpulmonary organ systems (neurologic, cardiovascular, renal and hematologic) using nonpulmonary PEdiatric Logistic Organ Dysfunction-2 (PELOD-20 scores.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: April 2, 2019)

• Interaction effects of prone positioning with HFOV on VFDs - number of ventilator-free days [ Time Frame: 28 days ]
  The number of ventilator-free days (VFD) will be compared between children randomized to prone/CMV and supine/HFOV to those randomized to prone/HFOV. VFD is the number of days within 28 days that a patient is alive and free of mechanical ventilation.
• 90-day in-hospital mortality [ Time Frame: 90 days ]
  Deaths from all causes will be monitored through hospital discharge or day 90 (whichever occurs first). The primary and secondary causes of death (as specified on the death certificate) will be recorded to allow us to probe the cause of death in PARDS.
• Duration of mechanical ventilation (among survivors) [ Time Frame: 28 days, 90 days ]
  Duration of mechanical ventilation provides a prospective evaluation of ventilator support independent of mortality. The duration of mechanical ventilation is defined as the time from day 0 (intubation) to the first time the endotracheal tube is continuously absent for at least 24 hours. For subjects with tracheostomies, duration of mechanical ventilation is defined as the time of initiation of assisted breathing to the first time positive pressure is <5 cm H2O (continuous or bi-level) for at least 24 hours. Duration of mechanical ventilation will be considered to be 28 days for subjects still intubated on day 28, and will be calculated for subjects who survive to hospital discharge or day 90 (whichever occurs first).
• PICU and hospital length of stay (among survivors) [ Time Frame: 90 days ]
  PICU length of stay (LOS) is defined as the time from day 0 (intubation) to the time of PICU discharge, while hospital LOS is defined as the time from day 0 to the time of hospital discharge. PICU and hospital LOS will be considered to be 90 days for subjects still in the PICU/hospital on day 90, and will be calculated for subjects who survive to hospital discharge or day 90 (whichever occurs first).
• Post PICU discharge functional status [ Time Frame: 1, 3, 6, 12 months post PICU discharge ]
  Pre and post PICU functional status will be compared. Functional status will be assessed using the Pediatric Cerebral Performance (PCPC), Pediatric Overall Performance Category (POPC) and Functional Status Scale (FSS) score. The PCPC and POPC quantify short-term cognitive impairments and functional morbidity. Scores range from 1 to 6 for both scales with 1: good, 2: mild disability, and 6: brain death. The FSS is a valid and reliable assessment method to quantify functional status. The FSS includes 6 domains: mental status, sensory functioning, communication, motor function, feeding, and respiratory. Scores for each domain range from 1 (normal) to 5 (very severe dysfunction) with total scores ranging from 6 to 30.
• Post PICU discharge health-related quality of life (HRQL) [ Time Frame: 1, 3, 6, 12 months post PICU discharge ]
  Pre and post PICU health-related quality of life will be compared using the PedsQL 4.0 Generic Core Scales and Infant Scales - Acute Version They are 23-item child self-report and parent proxy-report scales with four domains: physical functioning, emotional functioning, social functioning, and school functioning. Scale ranges from 0 to 100, with higher scores indicating fewer problems. The PedsQL Infant Scales consist of 36-45 questions, depending on age, with 5 domains: physical functioning, physical symptoms, emotional functioning, social functioning, and cognitive functioning. The PedsQL™ Multi-dimensional Fatigue Scale - Acute Version is an 18-item scale that encompasses three domains: General Fatigue, Sleep/Rest Fatigue and Cognitive Fatigue. Higher scores indicate better HRQOL. PedsQL Pediatric Pain Questionnaire is a generic pain instrument. Subjects capable of self-reporting identify a point on a 100 mm line that best shows the worst pain they experienced in the past week.

Original Other Pre-specified Outcome Measures (submitted: March 27, 2019)

• Interaction effects between the positioning and ventilation strategies [ Time Frame: 28 days ]
  We will evaluate possible interaction effects of prone positioning with HFOV on VFD, which will allow us to probe for potential differential effects when these two interventions are used concurrently.
• 90-day in-hospital mortality [ Time Frame: 90 days ]
  Deaths from all causes will be monitored through hospital discharge or day 90 (whichever occurs first). The primary and secondary causes of death (as specified on the death certificate) will be recorded to allow us to probe the cause of death in PARDS.
• Duration of mechanical ventilation (among survivors) [ Time Frame: 28 days, 90 days ]
  Duration of mechanical ventilation provides a prospective evaluation of ventilator support independent of mortality. The duration of mechanical ventilation is defined as the time from day 0 (intubation) to the first time the endotracheal tube is continuously absent for at least 24 hours. For subjects with tracheostomies, duration of mechanical ventilation is defined as the time of initiation of assisted breathing to the first time positive pressure is <5 cm H2O (continuous or bi-level) for at least 24 hours. Duration of mechanical ventilation will be considered to be 28 days for subjects still intubated on day 28, and will be calculated for subjects who survive to hospital discharge or day 90 (whichever occurs first).
• PICU and hospital length of stay (among survivors) [ Time Frame: 90 days ]
  PICU length of stay (LOS) is defined as the time from day 0 (intubation) to the time of PICU discharge, while hospital LOS is defined as the time from day 0 to the time of hospital discharge. PICU and hospital LOS will be considered to be 90 days for subjects still in the PICU/hospital on day 90, and will be calculated for subjects who survive to hospital discharge or day 90 (whichever occurs first).
• Post PICU discharge functional status [ Time Frame: 1, 3, 6, 12 months post PICU discharge ]
  Pre and post PICU functional status will be compared. Functional status will be assessed using the Pediatric Cerebral Performance (PCPC), Pediatric Overall Performance Category (POPC) and Functional Status Scale (FSS) score. The PCPC and POPC quantify short-term cognitive impairments and functional morbidity. Scores range from 1 to 6 for both scales with 1: good, 2: mild disability, and 6: brain death. The FSS is a valid and reliable assessment method to quantify functional status. The FSS includes 6 domains: mental status, sensory functioning, communication, motor function, feeding, and respiratory. Scores for each domain range from 1 (normal) to 5 (very severe dysfunction) with total scores ranging from 6 to 30.
• Post PICU discharge health-related quality of life (HRQL) [ Time Frame: 1, 3, 6, 12 months post PICU discharge ]
  Pre and post PICU health-related quality of life will be compared using the PedsQL 4.0 Generic Core Scales and Infant Scales - Acute Version They are 23-item child self-report and parent proxy-report scales with four domains: physical functioning, emotional functioning, social functioning, and school functioning. Scale ranges from 0 to 100, with higher scores indicating fewer problems. The PedsQL Infant Scales consist of 36-45 questions, depending on age, with 5 domains: physical functioning, physical symptoms, emotional functioning, social functioning, and cognitive functioning. The PedsQL™ Multi-dimensional Fatigue Scale - Acute Version is an 18-item scale that encompasses three domains: General Fatigue, Sleep/Rest Fatigue and Cognitive Fatigue. Higher scores indicate better HRQOL. PedsQL Pediatric Pain Questionnaire is a generic pain instrument. Subjects capable of self-reporting identify a point on a 100 mm line that best shows the worst pain they experienced in the past week.

Descriptive Information

• Brief Title: PROSpect: Prone and Oscillation Pediatric Clinical Trial
• Official Title: PROSpect: Prone and Oscillation Pediatric Clinical Trial
• Brief Summary: Severe pediatric acute respiratory distress syndrome (PARDS) is a life-threatening and frequent problem experienced by thousands of children each year. Little evidence supports current supportive practices during their critical illness. The overall objective of this study is to identify the best positional and/or ventilation practice that leads to improved patient outcomes in these critically ill children. We hypothesize that children with high moderate-severe PARDS treated with either prone positioning or high-frequency oscillatory ventilation (HFOV) will demonstrate more days off the ventilator when compared to children treated with supine positioning or conventional mechanical ventilation (CMV).
• Detailed Description: PROSpect is a two-by-two factorial, response-adaptive, randomized controlled clinical trial of supine/prone positioning and conventional mechanical ventilation (CMV)/high-frequency oscillatory ventilation (HFOV). About 60 pediatric intensive care units (PICUs), two thirds U.S. and one third international, with at least 5 years of experience with prone positioning and HFOV in the care of pediatric patients with severe Pediatric Acute Respiratory Distress Syndrome (PARDS), that can provide back-up extracorporeal membrane oxygenation (ECMO) support, are participating. Eligible consecutive subjects with high moderate-severe PARDS will be randomized to one of four groups: supine/CMV, prone/CMV, supine/HFOV, prone/HFOV. Subjects who fail their assigned positional and/or ventilation therapy for either persistent hypoxia or hypercapnia may receive the reciprocal therapy while being considered for ECMO cannulation. Our primary outcome is ventilator-free days (VFD) through day 28, where non-survivors receive zero VFD. We hypothesize that children with severe PARDS treated with either prone positioning or HFOV will demonstrate ≥ 2 more VFD. Our secondary outcome is nonpulmonary organ failure-free days. We will also explore the interaction effects of prone positioning with HFOV on VFDs and also investigate the impact of these interventions on 90-day in-hospital mortality and, among survivors, the duration of mechanical ventilation, PICU and hospital length of stay, and the trajectory of post-PICU functional status and health-related quality of life (HRQL). Up to 800 subjects with severe PARDS will be randomized, stratified by age group and direct/indirect lung injury. Adaptive randomization will first occur after 300 patients are randomized and have been followed for 28 days, and every 100 patients thereafter. At these randomization update analyses, new allocation probabilities will be computed based on ongoing intention-to-treat trial results, increasing allocation to well performing arms and decreasing allocation to poorly performing arms. Data will be analyzed per intention-to-treat for the primary analyses and per-protocol received for primary, secondary and exploratory analyses.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:

Two-by-two factorial, response-adaptive, randomized controlled clinical trial

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Acute Respiratory Distress Syndrome in Children

Intervention

Other: Either supine or prone positioning and either CMV or HFOV

Supine positioning: Subjects randomized to supine positioning will remain supine.

Prone positioning: Subjects randomized to prone positioning will be positioned prone ≥16 hours/day for a maximum of 28 days.

CMV strategy: Low tidal volume to obtain exhaled Vt of 5-7 ml/kg (ideal body weight), PIP goal limited to ≤ 28 cm H2O and lung recruitment maneuver to identify best PEEP then maintained per PEEP-FiO2 grid.

HFOV strategy: Frequency at 8-12 Hz, amplitude (delta-P) 60-90 and mPaw recruitment maneuver.

Other Names:

• Supine positioning
• Prone positioing
• Conventional mechanical ventilation (CMV)
• High frequency oscillatory ventilation (HFOV)

Study Arms

• Experimental: Supine / CMV
  Supine positioning and conventional mechanical ventilation
  Intervention: Other: Either supine or prone positioning and either CMV or HFOV
• Experimental: Prone / CMV
  Prone positioning and conventional mechanical ventilation
  Intervention: Other: Either supine or prone positioning and either CMV or HFOV
• Experimental: Supine / HVOF
  Supine positioning and high-frequency oscillatory ventilation
  Intervention: Other: Either supine or prone positioning and either CMV or HFOV
• Experimental: Prone / HFOV
  Prone positioning and high-frequency oscillatory ventilation
  Intervention: Other: Either supine or prone positioning and either CMV or HFOV

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Enrolling by invitation
• Estimated Enrollment (submitted: June 13, 2022): 800
• Original Estimated Enrollment (submitted: March 27, 2019): 1000
• Estimated Study Completion Date: July 31, 2026
• Estimated Primary Completion Date: January 1, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

Intubated and mechanically ventilated with high moderate-severe PARDS for <48 hours per PALICC guidelines (chest imaging consistent with acute pulmonary parenchymal disease and OI ≥12 or OSI ≥10). We require two blood gases meeting moderate-severe PARDS criteria (separated by at least 4 ± 2 hours during which time the clinical team is actively working to recruit lung volume and optimize the patient's hemodynamic status per PALICC guidelines; specifically, incremental and decremental PEEP changes to optimize lung volume). A second blood gas is not required for OI ≥16.

Exclusion criteria:

• Perinatal related lung disease
• Congenital diaphragmatic hernia or congenital/acquired diaphragm paralysis
• Respiratory failure explained by cardiac failure or fluid overload
• Cyanotic heart disease
• Cardiomyopathy
• Unilateral lung disease
• Primary pulmonary hypertension
• Intubated for status asthmaticus
• Obstructive airway disease (e.g., Severe airways disease without parenchymal involvement or disease characterized by hypercapnia with FiO2 <0.30 and/or evidence of increased resistance visible on the flow - time scalar and/or presence of intrinsic PEEP)
• Active air leak
• Bronchiolitis obliterans
• Post hematopoietic stem cell transplant; specifically, patients receiving continuous supplemental oxygen for three or more days prior to intubation; receiving noninvasive ventilation for more than 24 hours prior to intubation; receiving more than one vasoactive medication at time of meeting inclusion criteria; spending more than four days in the PICU prior to intubation; supported on or with immediate plans for renal replacement therapies; with two or more allogeneic transplants; who relapsed after the transplant; or with diffuse alveolar hemorrhage
• Post lung transplant
• Home ventilator dependent with baseline Oxygen Saturation Index (OSI) >6
• Neuromuscular respiratory failure
• Critical airway (e.g., post laryngotracheal surgery or new tracheostomy) or anatomical obstruction of the lower airway (e.g., mediastinal mass)
• Facial surgery or trauma in previous 2 weeks
• Head trauma (managed with hyperventilation)
• Intracranial bleeding
• Unstable spine, femur or pelvic fractures
• Open abdomen
• Currently receiving either prone positioning or any high-frequency mode of MV with current illness (Up to 4 hours of prone positioning and/or any mode of high-frequency mode of MV is allowed as long as the therapies are off for least 4 hours prior to the subject meeting oxygenation criteria.)
• Supported on ECMO during the current admission
• Family/medical team not providing full support (patient treatment considered futile)
• Previously enrolled in current study
• Enrolled in any other interventional clinical trial not approved for co-enrollment
• Known pregnancy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Weeks to 20 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Canada, China, India, Italy, Malaysia, Netherlands, New Zealand, Thailand, United Arab Emirates, United Kingdom, United States

Administrative Information

• NCT Number: NCT03896763
• Other Study ID Numbers: 831295; 5UH3HL141736-03 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Per NHLBI policy, we will provide a deidentified dataset and all the data-related documentation necessary to utilize the study data (dictionary, calculated variables and standard operating procedures) to the NHLBI. We will submit this dataset to the NHLBI Data Repository managed by the BioLINCC (Biologic Specimen and Data Repository Information Coordinating Center).
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: 3 years after the final follow-up interview or 2 years after the primary paper has been published, whichever comes first.
• Access Criteria: Subject to the approval of the (1) PROSpect Ancillary Study Committee, (2) PROSpect Executive Committee, and (3) National Heart, Lung, and Blood Institute (NHLBI).

• Current Responsible Party: Martha A.Q. Curley, PhD, RN, University of Pennsylvania
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Pennsylvania
• Original Study Sponsor: Same as current

Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• University Medical Center Groningen
• Boston Children's Hospital
• University Hospitals Cleveland Medical Center

Investigators

• Principal Investigator: Martha AQ Curley, RN, PhD; University of Pennsylvania
• Principal Investigator: Ira M. Cheifetz, MD; UH Rainbow Babies and Children's Hospital
• Principal Investigator: Martin CJ Kneyber, MD, PhD; Beatrix Children's Hospital
• Principal Investigator: David Wypij, PhD; Boston Children's Hospital

• PRS Account: University of Pennsylvania
• Verification Date: August 2022