Platform of Randomized Adaptive Clinical Trials in Critical Illness

Not Applicable

Recruiting

Conditions: Respiratory Insufficiency
Extracorporeal Membrane Oxygenation Complication
Mechanical Ventilation Pressure High

Interventions: Other: Ultra-Protective Ventilation Facilitated by Extracorporeal Support
Drug: Early Cohort corticosteroid dose
Drug: Extended Cohort corticosteroid dose
Other: Driving Pressure-Limited Ventilation (DPL)
Other: Lung-Protective Ventilation (LPV)
Drug: Usual care without routine corticosteroids
Other: Lung- and Diaphragm-Protective Ventilation and Sedation (LDPVS)
Drug: Usual care without extending corticosteroids

Registration Number: NCT05440851

Lead Sponsor: University Health Network, Toronto

Brief Summary: PRACTICAL:

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).

ULTIMATE domain (currently enrolling):

The ULTIMATE pilot trial is a multi-center, randomized, open-label trial, embedded as a domain within the PRACTICAL platform trial. This domain will evaluate the effect of ultra-low intensity ventilation facilitated by CO2 removal through VV-ECMO versus best current conventional ventilation on all-cause hospital mortality among patients with early moderate-severe AHRF with high respiratory system elastance receiving potentially injurious mechanical ventilation.

Invasive Mechanical Ventilation (IMV) Strategies domain:

The IMV Strategies domain will evaluate multiple novel invasive ventilation strategies in comparison to conventional lung-protective ventilation in patients with acute hypoxemic respiratory failure (AHRF). Multiple approaches to mechanical ventilation are used, and the optimal approach is unknown. An efficient strategy to identify the best strategy is to compare multiple potential approaches simultaneously to determine more rapidly (a) which interventions are least effective (and should be dropped), and (b) which interventions result in the best outcomes for patients. In the current domain design, we will compare the current recommended ventilation strategy to two new approaches: a strategy that targets lung-inflating (driving) pressure instead of lung-inflating (tidal) volume, and a strategy that aims to maintain an optimal level of breathing effort to prevent diaphragm atrophy and injury while maintaining safe lung-inflating pressures.

CORT-E2:

The Corticosteroid Early and Extended (CORT-E2) Trial is a phase III, multicentre Bayesian randomized controlled trial (RCT), which includes two cohorts within the domain; one examining the role of early corticosteroids as compared to not extending in persisting AHRF due to COVID or non-COVID (Extended Cohort).

Detailed Description: 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.

Interventions will be evaluated within therapeutic domains. 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. Domains are intended to function independently of each other, allowing independent evaluation of multiple therapies 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.

Recruitment & Eligibility

Status: RECRUITING

Sex: All

Target Recruitment: 6250

Inclusion Criteria

Acute hypoxemic respiratory failure meeting all of the following criteria;
1. New or worsening respiratory symptoms developing within 2 weeks prior to the onset of need for oxygen or respiratory support
2. Receiving any of the following types of oxygen or respiratory support for at least 4 hours prior to the time of randomization; supplemental oxygen at 10 L/min or higher, high flow nasal oxygen (at any flow rate), invasive ventilator support, extra-corporeal life support (ECLS), or non-invasive ventilator support
3. Minimum FiO2 ≥ 0.40 (for venturi mask, high flow nasal cannula, or invasive or non-invasive ventilation) or oxygen flow rate ≥10 L/min on face mask for at least 4 hours at the time of evaluation for eligibility unless already on extra- corporeal life support
Age ≥ 18 years
Hypoxemia not primarily attributable to acute heart failure, fluid overload, or pulmonary embolism (PE)

PRACTICAL Platform

Exclusion Criteria

Extubation is planned or anticipated on the day of screening
ICU discharged is planned or anticipated on the day of screening
If the patient is moribund and deemed unlikely to survive 24 hours (as determined by the clinical team)
If the patient is being transitioned to a fully palliative philosophy of care

ULTIMATE Domain Inclusion Criteria:

Endotracheal mechanical ventilation for ≤5 days
Early moderate-severe hypoxemic respiratory failure with a PaO2/FiO2≤200 mmHg for at least 6 hours

ULTIMATE Domain Exclusion Criteria:

Patients over 65 years of age
Currently receiving any form of ECMO (ex. venovenous, venoarterial, or hybrid configuration)
Δ PL-dyn ≤20 or Static Δ P≤15 cm H2O while receiving VT 6mL/kg (i.e. normalized elastance ≤ 2.5 cmH2O/mL/kg)
Chronic hypercapnic respiratory failure defined as PaCO2>60mmHg in the outpatient setting
Home mechanical ventilation (non-invasive ventilation or via tracheotomy), not CPAP
Actual body weight exceeding 1kg per centimeter of height
More than 48 hours have passed since meeting inclusion criteria
Severe hypoxemia with PaO2/FiO2<80mmHg for >6 hours at time of screening
Severe hypercapnic respiratory failure with pH<7.25 and PaCO2>60mmHg for >6 hours at time of screening
Expected mechanical ventilation duration <48 hours at time of screening
Confirmed diffuse alveolar hemorrhage from vasculitis
Contraindications to limited anticoagulation (ex. active GI bleeding, bleeding diathesis)
Pregnancy-due to unknown effects of PaCO2 changes on placental blood flow
Respiratory Failure known or suspected to be caused by COVID-19

IMV Domain Inclusion Criteria:

Intubated patients, not on ECLS, with low normalized respiratory elastance (<2.5 cm H2O/(ml/kg predicted body weight)) at the time of eligibility assessment OR
Intubated patients, not on ECLS, with high normalized respiratory system elastance (≥2.5 cm H2O/(ml/kg predicted body weight)) at the time of eligibility assessment OR
FOR STUDY SITES PARTICIPATING IN THE LDPVS INTERVENTION: Patient is on ECLS at the time of eligibility assessment. Note: Patients in this state are only eligible for the LPV or LDPVS intervention

IMV Domain Exclusion Criteria:

PaO2/FiO2 >300 mm Hg or (S/F >250, if PaO2/FiO2 has not been measured) at the time of randomization
Chronic hypercapnic respiratory failure defined as PaCO2>60mmHg in the outpatient setting
Home mechanical ventilation (non-invasive ventilation or via tracheotomy), not including nocturnal CPAP applied by nasal or face mask or home tracheotomy if not ventilated
Severe hypoxemia with PaO2/FiO2<80mmHg for >6 consecutive hours at the time of randomization
Severe hypercapnic respiratory failure with pH<7.25 and PaCO2>60mmHg for >6 consecutive hours at the time of randomization
Anticipated duration of mechanical ventilation is <48 hours from the time of screening
Duration of mechanical ventilation during current ICU admission is >72 hours
Previously diagnosed neuromuscular disorder
Current diagnosis of severe acute brain injury (e.g. ischemic or hemorrhagic stroke, traumatic brain injury) with Glasgow Coma Scale ≤ 8
Baseline weight prior to or at hospital admission less than 35 kilograms
Receiving extracorporeal life support without continuous invasive mechanical ventilatory support

CORT-E2 Domain Early Cohort Inclusion Criteria

Within 72 hours of admission to an ICU
New unilateral or bilateral airspace disease

CORT-E2 Domain Early Domain Exclusion Criteria

Receiving only low flow oxygen therapy less than or equal to 15L/min
Corticosteroid use during the 14 days prior to screening
Existing indication for corticosteroids
High suspicion for/or confirmed COVID infection
Acute traumatic brain injury during the index hospital admission
Allergy to dexamethasone

CORT-E2 Domain Extended Cohort Inclusion Criteria

Are admitted to an ICU
Have already received 10 days of corticosteroid specifically for acute respiratory failure, this will include patients: (a) randomized to corticosteroid arm in Early Cohort, (b) patients with COVID receiving corticosteroids as standard of care , (c) and others who have received corticosteroids for AHRF
Ongoing AHRF requiring HFNC, NIV (continuous positive airway pressure [CPAP] or bilevel) or invasive ventilation

CORT-E2 Domain Extended Cohort Exclusion Criteria

An alternate indication for ongoing corticosteroids
Acute traumatic brain injury this hospital admission

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ultra-protective ventilation facilitated by extracorporeal carbon dioxide removal (ULTIMATE) domain	Ultra-Protective Ventilation Facilitated by Extracorporeal Support	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 conventional lung-protective ventilation.
The Corticosteroid Early and Extended (CORT-E2) Randomized Controlled Trial domain	Extended Cohort corticosteroid dose	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.
The Corticosteroid Early and Extended (CORT-E2) Randomized Controlled Trial domain	Usual care without extending corticosteroids	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.
Invasive Mechanical Ventilation (IMV) Strategies domain	Driving Pressure-Limited Ventilation (DPL)	Patients on invasive mechanical ventilation in the low elastance, high elastance, and ECLS states will be randomized to one of two or three 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 arms.
The Corticosteroid Early and Extended (CORT-E2) Randomized Controlled Trial domain	Usual care without routine corticosteroids	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.
Ultra-protective ventilation facilitated by extracorporeal carbon dioxide removal (ULTIMATE) domain	Lung-Protective Ventilation (LPV)	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 conventional lung-protective ventilation.
Invasive Mechanical Ventilation (IMV) Strategies domain	Lung- and Diaphragm-Protective Ventilation and Sedation (LDPVS)	Patients on invasive mechanical ventilation in the low elastance, high elastance, and ECLS states will be randomized to one of two or three 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 arms.
The Corticosteroid Early and Extended (CORT-E2) Randomized Controlled Trial domain	Early Cohort corticosteroid dose	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.
Invasive Mechanical Ventilation (IMV) Strategies domain	Lung-Protective Ventilation (LPV)	Patients on invasive mechanical ventilation in the low elastance, high elastance, and ECLS states will be randomized to one of two or three 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 arms.

Primary Outcome Measures

Name	Time	Method
IMV domain - probability of achieving and maintaining lung- and diaphragm-protective targets during mechanical ventilation (LANDMARK RCT)	Day 28	Lung- and diaphragm-protective targets are defined as an estimated dynamic trans pulmonary driving pressure ≤23 cm H2O and a Pocc value between -6 to -20 cm H2O.
ULTIMATE domain - determine the feasibility of recruiting 72 patients over 1 year of active enrolment, as well as assess the rate of participant recruitment and understand the barriers to enrollment.	1 year of active site enrollment.	Record total number of patients randomized, total number of patients eligible yet not randomized, and the number of active randomizing sites on a monthly basis. This will include evaluating the validity and appropriateness of inclusion and exclusion criteria, trial acceptability, and reasons for lack of consent or withdrawal.
IMV domain - adherence to LDPVS management (LANDMARK RCT)	Day 28	Adherence to LDPVS management will be measured in terms of the proportion of protocol-specified measurements of respiratory effort that are on target during the intervention period.
CORT-E2 domain - 60-day mortality from the day of randomization	Day 60
IMV domain - ventilator-free days to day 28 in DPL vs LPV (DRIVE RCT)	Day 28 post randomization	Ventilator-free days to day 28 is computed as an ordinal scale ranging between -1 to 28. Patients who die in hospital will be assigned a value of -1. Otherwise the endpoint will be computed from the number of days alive and free of ventilation in the period between the day the patient is liberated from mechanical ventilation and day 28.

Secondary Outcome Measures

Name	Time	Method
Duration of supplemental oxygen use	Until ICU discharge, typically within 28 days	Measured in CORT-E2 domain
To measure and understand the reasons for crossovers in each group	1 year	Measured in ULTIMATE domain. Assess the proportion of crossovers consistent with, or in violation of, the study protocol and thoroughly understand the reasons for these events through detailed questionnaires and descriptive case report forms.
Duration of mechanical ventilation during index ICU admission	Until ICU discharge, typically within 28 days	Measured in CORT-E2, IMV, and ULTIMATE domains
Duration of ECLS, only for patients who require ECLS	Until ICU discharge, typically within 28 days	Measured in CORT-E2 domain
EQ-5-D at day 180	Day 180	Measured in CORT-E2, IMV domains
Hospital length of stay	Until hospital discharge, assessed up to 4 weeks	Measured in CORT-E2, IMV domains
Need for ICU readmission prior to hospital discharge	Until hospital discharge, assessed up to 4 weeks	Measured in IMV domain
Sequential Organ Failure Assessment (SOFA) score	Daily, for duration of intervention	Measured in IMV domain
Respiratory mechanics and gas exchange - Driving pressure.	Daily, for duration of intervention	Measured in IMV domain.
Respiratory mechanics and gas exchange - Pocc.	Daily, for duration of intervention	Measured in IMV domain.
Respiratory mechanics and gas exchange - P0.1	Daily, for duration of intervention	Measured in IMV domain.
Mortality at other endpoints	ICU discharge, hospital discharge, day 30, 180 days	Measured in CORT-E2, IMV, and ULTIMATE domains
Duration of NIV	Until ICU discharge, typically within 28 days	Measured in CORT-E2 domain
To assess adherence to our explicit mechanical ventilation protocols, with particular focus on delivered tidal volumes in both groups and estimated ΔPL-dyn in the ECMO group.	48 hours	Measured in ULTIMATE domain. Evaluate number of protocol violations and their causes (control group: VT\>8mL/kg, PPLAT\>30cm H2O; experimental group: VT\>8mL/kg, PPLAT\>30cm H2O, ΔPL-dyn \>20 cm H2O) over 2 consecutive data points for a minimum of 48 hours.
Duration of ICU admission	Until ICU discharge, typically within 28 days	Measured in IMV and ULTIMATE domains
Discharge disposition.	Until hospital discharge, assessed up to 4 weeks	Measured in IMV domain. Location to which patient is discharged (e.g., home, weaning facility, etc.)
Days alive and at home to day 90	Day 90	Measured in IMV domain
Need for ECLS	Until ICU discharge, typically within 28 days	Measured in CORT-E2 domain
Complications from corticosteroids.	Until hospital discharge, assessed up to 4 weeks	Measured in CORT-E2 domain. Hypernatremia, hyperglycemia, delirium, clinically important GI bleeding, nosocomial infection, neuromuscular weakness
Diaphragm thickness	Daily, for duration of intervention	Measured in IMV domain
Respiratory mechanics and gas exchange - ventilatory ratio	Daily, for duration of intervention	Measured in IMV domain.
Survival status at disconnection from mechanical ventilation (dead or alive)	Until day 28	Measured in ULTIMATE domain
Ventilator-free days until day 30 for CORT-E2, and until day 28 for ULTIMATE (an ordinal scale composed of survival to hospital discharge and days alive and free of ventilation where death in the hospital is assigned a score of -1).	Until day 30 for CORT-E2, and until day 28 for ULTIMATE	Measured in CORT-E2 and ULTIMATE domains.
Reintubation during index ICU admission	Until ICU discharge, typically within 28 days	Measured in IMV domain
Tracheostomy during index ICU admission	Until ICU discharge, typically within 28 days	Measured in IMV domain
Maximal diaphragm thickening fraction	During first SBT	Measured in IMV domain
Respiratory mechanics and gas exchange - plateau airway pressure	Daily, for duration of intervention	Measured in IMV domain.
Respiratory mechanics and gas exchange - P/F ratio	Daily, for duration of intervention	Measured in IMV domain.

Trial Locations

Locations (1): University Health Network
🇨🇦
Toronto, Canada

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