Platform of Randomized Adaptive Clinical Trials in Critical Illness

Summary

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.

Conditions

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

Interventions

OTHER

no treatment / intervention arm is involved

This trial is a prospective, multicenter, observational study (no treatment arm is involved).

OTHER

Usual care

Patients will be treated according to usual care.

OTHER

Ultra-Protective Ventilation Facilitated by Extracorporeal Support

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.

OTHER

Lung-Protective Ventilation (LPV)

Patients randomized to LPV will receive standard of care lung-protective ventilation with conventional limits on tidal volume and plateau airway pressure.

OTHER

Driving Pressure-Limited Ventilation (DPL)

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.

OTHER

Lung- and Diaphragm-Protective Ventilation and Sedation (LDPVS)

Patients randomized to LDPVS will have ventilation and sedation adjusted to maintain lung-distending pressure and respiratory effort in a safe target range.

DRUG

Early Cohort corticosteroid dose

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.

DRUG

Extended Cohort corticosteroid dose

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).

DRUG

Usual care without routine corticosteroids

Patients randomized to this arm will be managed according to usual care. They will receive corticosteroids only if prescribed by the clinician.

DRUG

Usual care without extending corticosteroids

Corticosteroids will stop after 10 days. Other management will be according to usual care. Patients will receive corticosteroids only if prescribed by the clinician.

DRUG

Usual care with fludrocortisone

Best practice standard of care prescribed by treating team + fludrocortisone 50μg enterally daily for 7 days.

DRUG

Usual care without fludrocortisone

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

Drug 4 mL:

4 mL of nebulized 0.9% saline minutes every 6 hours over 30 minutes every 6 hours.

DRUG

Drug 40 mg:

40 mg of nebulized furosemide in 4 mL of saline nebulized over 30 minutes every 6 hours

OTHER

PEEP-20

fixed high positive end-expiratory pressure at 20 cmH2O

OTHER

PEEP-AOP

positive end-expiratory pressure set according to airway opening pressure

OTHER

PEEP-10

fixed lower positive end-expiratory pressure at 10 cmH2O

OTHER

VV ECMO-facilitated strategy of earlier awakening, extubation and rehabilitation

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.

OTHER

Electrical impedance tomography (EIT)

Patients randomized to EIT will have PEEP titration compared via the Overdistension Collapse Intercept (ODCL) versus that obtained using a standard high PEEP table.

OTHER

Early Routine IMT

* 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.

OTHER

no treatment / intervention arm is involved.

This trial is a prospective, multicenter, observational study (no treatment arm is involved).

Sponsors & Collaborators

• University Health Network, Toronto

  lead OTHER

Principal Investigators

• Ewan Goligher, MD, PhD · University Health Network, Toronto

• Eddy Fan, MD, PhD · University Health Network, Toronto

• Niall Ferguson, MD, MSc · University Health Network, Toronto

• Lorenzo Del Sorbo, MD · University Health Network, Toronto

• Bram Rochwerg, MD, MSc · McMaster University

• Bijan Teja, MD · Unity Health Toronto

• John Muscedere, MD · Queens University

• Laveena Munshi, MD · Mount Sinai Hospital, Canada

• Dmitry Rozenberg, MD, PhD · University Health Network, Toronto

• Anastasia Newman, PhD · McMaster University

• Irene Telias, MD, PhD · University Health Network, Toronto

• Andrea Castellvi Font, MD, PhD · Parc de Salut Mar, Spain

• Laurent Brochard, MD · Unity Health Toronto

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2023-04-30

Primary Completion

2027-03-31

Completion

2027-03-31

Countries

• United States
• Australia
• Canada
• Colombia
• Italy
• New Zealand
• Saudi Arabia
• Singapore
• Spain

Study Locations