Platform of Randomized Adaptive Clinical Trials in Critical Illness

Conditions

• Extracorporeal Membrane Oxygenation Complication
• Mechanical Ventilation Pressure High
• Respiratory Insufficiency

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• Ultra-Protective Ventilation Facilitated by Extracorporeal Support — OTHER
  Patients randomized to this intervention group will receive VV-ECMO with the ventilator set to minimize driving pressure and respiratory rate for ultra-protective ventilation.
• Lung-Protective Ventilation (LPV) — OTHER
  Patients randomized to LPV will receive standard of care lung-protective ventilation with conventional limits on tidal volume and plateau airway pressure.
• Driving Pressure-Limited Ventilation (DPL) — OTHER
  Patients randomized to DPL will receive mechanical ventilation set to maintain a safe limit on driving pressure and plateau airway pressure, without less for the tidal volume.
• Lung- and Diaphragm-Protective Ventilation and Sedation (LDPVS) — OTHER
  Patients randomized to LDPVS will have ventilation and sedation adjusted to maintain lung-distending pressure and respiratory effort in a safe target range.
• Early Cohort corticosteroid dose — DRUG
  Patients randomized to receive corticosteroids will receive dexamethasone 20mg daily for 5 days and then 10mg for an additional 5 days, for a total of 10 days from the time of randomization (or until ICU discharge or death, whichever comes first); after 10 days dexamethasone will be stopped without a taper.
• Extended Cohort corticosteroid dose — DRUG
  Patients randomized to receive extended corticosteroids will receive dexamethasone 10mg for an additional 10 days. At the end of the additional 10 days (day 20 of corticosteroids), the dexamethasone dose will be halved to 5mg for another 5 days (to reduce the risk of adrenal insufficiency) and then stopped (a total of 25 days or until ICU discharge or death, whichever comes first).
• Usual care without routine corticosteroids — DRUG
  Patients randomized to this arm will be managed according to usual care. They will receive corticosteroids only if prescribed by the clinician.
• Usual care without extending corticosteroids — DRUG
  Corticosteroids will stop after 10 days. Other management will be according to usual care. Patients will receive corticosteroids only if prescribed by the clinician.
• Usual care with fludrocortisone — DRUG
  Best practice standard of care prescribed by treating team + fludrocortisone 50μg enterally daily for 7 days.
• Usual care without fludrocortisone — DRUG
  Best practice standard of care prescribed by treating team without fludrocortisone. After randomization, if a clinical indication develops for fludrocortisone as part of standard of care, administration of fludrocortisone is not prohibited. Any fludrocortisone administered to participants in the control arm will be documented.
• Drug 4 mL: — DRUG
  4 mL of nebulized 0.9% saline minutes every 6 hours over 30 minutes every 6 hours.
• Drug 40 mg: — DRUG
  40 mg of nebulized furosemide in 4 mL of saline nebulized over 30 minutes every 6 hours
• PEEP-20 — OTHER
  fixed high positive end-expiratory pressure at 20 cmH2O
• PEEP-AOP — OTHER
  positive end-expiratory pressure set according to airway opening pressure
• PEEP-10 — OTHER
  fixed lower positive end-expiratory pressure at 10 cmH2O
• VV ECMO-facilitated strategy of earlier awakening, extubation and rehabilitation — OTHER
  Patients randomized to this intervention group will receive VV-ECMO where the sedation will be reduced and the ventilator will will be adjusted to facilitate spontaneous breathing.
• Electrical impedance tomography (EIT) — OTHER
  Patients randomized to EIT will have PEEP titration compared via the Overdistension Collapse Intercept (ODCL) versus that obtained using a standard high PEEP table.
• no treatment / intervention arm is involved — OTHER
  This trial is a prospective, multicenter, observational study (no treatment arm is involved).
• Usual care — OTHER
  Patients will be treated according to usual care.
• Early Routine IMT — OTHER
  * Training commences once patients meet readiness to wean criteria * 3 sets of 10 breaths, delivered twice daily using a device placed at the airway opening to apply an external resistive pressure load, until hospital discharge, death, or day 45 after randomization, whichever occurs first. * Device load will initially be set to 30% of the MIP. * Device load will be titrated upward (in increments of 5-10% of MIP, to a maximum of 60% of MIP) as needed to achieve a modified Borg dyspnea score of 7/10 or visible accessory muscle use.
• no treatment / intervention arm is involved. — OTHER
  This trial is a prospective, multicenter, observational study (no treatment arm is involved).

Study Details

PRACTICAL is a randomized multifactorial adaptive platform trial for acute hypoxemic respiratory failure (AHRF). This platform trial will evaluate novel interventions for patients with AHRF across a range of severity states (i.e., not intubated, intubated with lower or higher respiratory system elastance, requiring extracorporeal life support) and across a range of investigational phases (i.e., preliminary mechanistic trials, full-scale clinical trials). AHRF is a common and life-threatening clinical syndrome affecting millions globally every year. Patients with AHRF are at high risk of death and long-term morbidity. Patients who require invasive mechanical ventilation are at risk of ventilator-induced lung injury and ventilator-induced diaphragm dysfunction. New treatments and treatment strategies are needed to improve outcomes for these very ill patients. Utilizing advances in Bayesian adaptive trial design, the platform will facilitate efficient yet rigorous testing of new treatments for AHRF, with a particular focus on mechanical ventilation strategies and extracorporeal life support techniques as well as pharmacological agents and new medical devices. The platform is designed to enable evaluation of novel interventions at a variety of stages of investigation, including pilot and feasibility trials, trials focused on mechanistic surrogate endpoints for preliminary clinical evaluation, and full-scale clinical trials assessing the impact of interventions on patient-centered outcomes. A domain is defined as a set of interventions that are intended to act on specific mechanisms of injury using different variations of a common therapeutic strategy. A domain may also be a non-interventional study that addresses observational research questions by collecting specific data or outcomes that are not collected as part of other domains. Domains are intended to function independently of each other, allowing independent evaluation of multiple therapies and mechanistic pathways within the same patient. Once feasibility is established, Bayesian adaptive statistical modelling will be used to evaluate treatment efficacy at regular interim adaptive analyses of the pre-specified outcomes for each intervention in each domain. These adaptive analyses will compute the posterior probabilities of superiority, futility, inferiority, or equivalence for pre-specified comparisons within domains. Each of these potential conclusions will be pre-defined prior to commencing the intervention trial. Decisions about trial results (e.g., concluding superiority or equivalence) will be based on pre-specified threshold values for posterior probability. The primary outcome of interest, the definitions for superiority, futility, etc. (i.e., the magnitude of treatment effect) and the threshold values of posterior probability required to reach conclusions for superiority, futility etc., will vary from intervention to intervention depending on the phase of investigation and the nature of the intervention being evaluated. All of these parameters will be pre-specified as part of the statistical design for each intervention trial. In general, domains will be designed to evaluate treatment effect within four discrete clinical states: non-intubated patients, intubated patients with low respiratory system elastance (\<2.5 cm H2O/(mL/kg)), intubated patients with high respiratory system elastance (≥2.5 cm H2O/(mL/kg)), and patients requiring extracorporeal life support. Where appropriate, the model will specify dynamic borrowing between states to maximize statistical information available for trial conclusions. In this perpetual trial design, different interventions may be added or dropped over time. Where possible, the platform will be embedded within existing data collection repositories to enable greater efficiency in outcome ascertainment. Standardized systems for acquiring both physiological and biological measurements are embedded in the platform, to be acquired at sites with appropriate training, expertise, and facilities to collect those measurements.

Key Dates

Start date

Apr 30, 2023

Status verified

Dec 2025

Primary completion

Mar 31, 2027

Completion

Mar 31, 2027

Study Design

Enrollment

6,250 participants (estimated)

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Arms

• Other: Ultra-protective ventilation facilitated by extracorporeal carbon dioxide removal.
  Patients randomized to the this intervention group will receive VV-ECMO with the ventilator set to minimize driving pressure and respiratory rate for ultra-protective ventilation.
• Other: Invasive Mechanical Ventilation (IMV) Strategies domain
  Patients on invasive mechanical ventilation in the low elastance, high elastance, and ECLS states will be randomized to minimum of one of two mechanical ventilation interventions (including conventional lung-protective ventilation as a control group). Most sites will randomize patients to two arms (one of which is the control group, LPV). A subset of sites will randomize patients to all three or four arms.
• Other: The Corticosteroid Early and Extended (CORT-E2) Randomized Controlled Trial domain
  Patients with acute hypoxemic respiratory failure (AHRF) requiring invasive or non-invasive respiratory support will be randomized in the Early Cohort to receive corticosteroid or usual care without corticosteroids. Patients treated with corticosteroids who still require invasive or non-invasive respiratory support after 10 days will be randomized in the Extended Cohort to extending corticosteroid use or stopping corticosteroids after 10 days.
• Other: The Nebulized Furosemide for the Treatment of Pulmonary Inflammation (FAST-3) domain
  Patients with Respiratory Failure Secondary to Pulmonary Infection.
• Other: The Invasive Mechanical Ventilation Strategies in Venovenous-Extracorporeal Life Support (IMV-ECLS)
  Patients with acute hypoxemic respiratory failure receiving extracorporeal life support will be randomized to one of three positive end-expiratory pressure (PEEP) strategies.
• Other: The Fludrocortisone in Acute Hypoxemic Respiratory Failure with Airspace Disease (FLUDRO-1) domain
  Patients with acute hypoxemic respiratory failure with airspace disease will be randomized to usual care with or without fludrocortisone.
• Other: VV ECMO-facilitated strategy of earlier awakening, extubation and rehabilitation
  Patients with acute hypoxemic respiratory failure in the high elastance state will be randomized to ultra-protective ventilation facilitated by extracorporeal carbon dioxide removal or to VV ECMO-facilitated strategy of earlier awakening, extubation and rehabilitation or to conventional lung-protective ventilation.
• Other: Evaluating Subphenotypes in Immunocompromized Patients with ARF (ESCAPE) Domain
  We will conduct a prospective, multicenter, observational study (no treatment arm is involved) in 7 ICUs in Canada over 3 years. We will include adult patients (≥18 years) admitted to the ICU with AHRF who have an underlying immunocompromised condition. Biomarker Collection: Samples for serum biomarkers will be collected within 24 hours of fulfilling inclusion criteria, on days 0, 3 and 7. We will collect biomarkers associated with inflammatory conditions, epithelial injury, endothelial dysfunction and coagulation abnormalities - which have been shown to characterize lung injury or critical illness. Data Collection: We will collect demographic, comorbidity, immunocompromised defining condition, clinical, respiratory physiology, and serum biomarker data for each patient.
• Other: Inspiratory Muscle Training in Patients Receiving Ongoing Mechanical Ventilation (IMPROV) Domain
  This domain studies inspiratory muscle training (IMT) during and after mechanical ventilation in patients with acute hypoxemic respiratory failure (AHRF).
• Other: Clinical Implications of Potentially Injurious Patient-Ventilator Interactions (WAVEFORM) Domain
  This domain primarily aims at understanding the short-and long-term clinical consequences of longitudinal exposure to abnormal patient ventilator interactions.

Primary Outcome Measure

EXPAND-ECLS domain - determine the feasibility of recruiting 100 patients over 2 years of active enrolment, as well as assess the rate of participant recruitment and understand the barriers to enrollment. [ Time Frame: 2 years of active site enrollment. ]

Central Contacts

• Rongyu ( Cindy) Jin
  4163404800
  [email protected]
• Cathy Chau
  4167272260
  [email protected]

Locations (26)

Find similar trials in Tucson, AZ

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