Clinical trial NCT05440851: Platform of Randomized Adaptive Clinical Trials in Critical Illness
Official title: Platform of Randomized Adaptive Clinical Trials in Critical Illness
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Respiratory Insufficiency
Extracorporeal Membrane Oxygenation Complication
Mechanical Ventilation Pressure High
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
First posted: 2022-07-01
Enrollment: 6250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 :

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 domain:

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).

FLUDRO domain:

The Fludrocortisone in Acute Hypoxemic Respiratory Failure with Airspace Disease (FLUDRO-1) domain is a phase II I trial. The trial aims to provide direct clinical evidence to resolve a critical long-standing question regarding the use of steroids in the treatment of AHRF with airspace disease.

FAST-3:

The Nebulized Furosemide for the Treatment of Pulmonary Inflammation in Patients with Respiratory Failure Secondary to Pulmonary Infection domain is a phase III trial. It aims to use nebulized furosemide as supportive therapy to improve Advanced Respiratory Support (ARS) free days up to day 28 in critically ill patients with AHRF.

IMV-ECLS:

The Invasive Mechanical Ventilation Strategies in Venovenous-Extracorporeal Life Support (PRESSURE; Positive Pressure to Maintain Lung Recruitment during Extracorporeal Life Support for Acute Hypoxemic Respiratory failure) is a pilot and feasibility trial. It aims to identify which positive end-expiratory pressure (PEEP) strategies improve lung function in patients with AHRF supported by ECLS.

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.

Eligibility criteria: PRACTICAL Platform Inclusion Criteria:

1. 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
2. Age ≥ 18 years
3. Hypoxemia not primarily attributable to acute heart failure, fluid overload, or pulmonary embolism (PE)

PRACTICAL Platform Exclusion Criteria:

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

ULTIMATE Domain Inclusion Criteria:

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

ULTIMATE Domain Exclusion Criteria:

1. Patients over 65 years of age
2. Currently receiving any form of ECMO (ex. venovenous, venoarterial, or hybrid configuration)
3. 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)
4. Chronic hypercapnic respiratory failure defined as PaCO2\>60mmHg in the outpatient setting
5. Home mechanical ventilation (non-invasive ventilation or via tracheotomy), not CPAP
6. Actual body weight exceeding 1kg per centimeter of height
7. More than 48 hours have passed since meeting inclusion criteria
8. Severe hypoxemia with PaO2/FiO2\<80mmHg for \>6 hours at time of screening
9. Severe hypercapnic respiratory failure with pH\<7.25 and PaCO2\>60mmHg for \>6 hours at time of screening
10. Expected mechanical ventilation duration \<48 hours at time of screening
11. Confirmed diffuse alveolar hemorrhage from vasculitis
12. Contraindications to limited anticoagulation (ex. active GI bleeding, bleeding diathesis)
13. Pregnancy-due to unknown effects of PaCO2 changes on placental blood flow
14. Respiratory Failure known or suspected to be caused by COVID-19

IMV Domain Inclusion Criteria:

1. 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
2. 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
3. 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:

1. PaO2/FiO2 \>300 mm Hg or (S/F \>250, if PaO2/FiO2 has not been measured) at the time of randomization
2. Chronic hypercapnic respiratory failure defined as PaCO2\>60mmHg in the outpatient setting
3. 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
4. Severe hypoxemia with PaO2/FiO2\<80mmHg for \>6 consecutive hours at the time of randomization
5. Severe hypercapnic respiratory failure with pH\<7.25 and PaCO2\>60mmHg for \>6 consecutive hours at the time of randomization
6. Anticipated duration of mechanical ventilation is \<48 hours from the time of screening
7. Duration of mechanical ventilation during current ICU admission is \>72 hours
8. Previously diagnosed neuromuscular disorder
9. Current diagnosis of severe acute brain injury (e.g. ischemic or hemorrhagic stroke, traumatic brain injury) with Glasgow Coma Scale ≤ 8
10. Baseline weight prior to or at hospital admission less than 35 kilograms
11. Receiving extracorporeal life support without continuous invasive mechanical ventilatory support

CORT-E2 Domain Early Cohort Inclusion Criteria

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

CORT-E2 Domain Early Domain Exclusion Criteria

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

CORT-E2 Domain Extended Cohort Inclusion Criteria

1. Are admitted to an ICU
2. 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
3. Ongoing AHRF requiring HFNC, NIV (continuous positive airway pressure \[CPAP\] or bilevel) or invasive ventilation

CORT-E2 Domain Extended Cohort Exclusion Criteria

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

Primary outcomes:
measure: 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.
timeFrame: 1 year of active site enrollment.
measure: FLUDRO-1 and IMV domains - ventilator-free days to day 28 in DPL vs LPV (DRIVE RCT)
timeFrame: Day 28 post randomization
measure: IMV domain - adherence to LDPVS management (LANDMARK RCT)
timeFrame: Day 28
measure: IMV domain - probability of achieving and maintaining lung- and diaphragm-protective targets during mechanical ventilation (LANDMARK RCT)
timeFrame: Day 28
measure: CORT-E2 domain - 60-day mortality from the day of randomization
timeFrame: Day 60
measure: FLUDRO-1 domain - Successful enrollment of participants
timeFrame: 18-month enrolment period across three platform trials (PRACTICAL, REMAP-CAP and ATTACC-CAP)
measure: FAST-3 domain - Advanced respiratory support free days
timeFrame: Day 28
measure: IMV-ECLS domain - feasibility of enrollment and protocol adherence
timeFrame: For feasibility of enrollment: 2 years of active site enrollment; For protocol adherence, these will be evaluated at 7 days (once the intervention period ends)
Secondary outcomes:
measure: 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.
timeFrame: 48 hours
measure: To measure and understand the reasons for crossovers in each group
timeFrame: 1 year
measure: Duration of mechanical ventilation during index ICU admission
timeFrame: Until ICU discharge, typically within 28 days
measure: Mortality at other endpoints
timeFrame: ICU discharge, hospital discharge, day 30, 180 days for CORT-E2, IMV, IMV-ECLS, and ULTIMATE domains. For FAST-3, all-cause mortality at 60 days post enrollment.
measure: Duration of ICU admission
timeFrame: Until ICU discharge, typically within 28 days
measure: Hospital length of stay
timeFrame: Until hospital discharge, assessed up to 4 weeks
measure: ICU and hospital free days
timeFrame: ICU discharge, hospital discharge, Day 28.
measure: Discharge disposition.
timeFrame: Until hospital discharge, assessed up to 4 weeks
measure: Days alive and at home to day 90
timeFrame: Day 90
measure: Need for ICU readmission prior to hospital discharge
timeFrame: Until hospital discharge, assessed up to 4 weeks
measure: Duration of NIV
timeFrame: Until ICU discharge, typically within 28 days
measure: Duration of supplemental oxygen use
timeFrame: Until ICU discharge, typically within 28 days
measure: Need for ECLS
timeFrame: Until ICU discharge, typically within 28 days
measure: Duration of ECLS, only for patients who require ECLS
timeFrame: Until ICU discharge, typically within 28 days
measure: Ventilator-free days until day 30 for CORT-E2, and until day 28 for FAST-3, FLUDRO-1 and ULTIMATE (an ordinal scale composed of survival to hospitaldischarge and days alive and free of ventilation where death in the hospital is assigned a score of -1).
timeFrame: Until day 30 for CORT-E2, and until day 28 for FAST-3, FLUDRO-1 and ULTIMATE
measure: EQ-5-D at day 180
timeFrame: Day 180
measure: Montreal Cognitive Assessment (MoCA) At day 180
timeFrame: Day 180
measure: Complications from corticosteroids.
timeFrame: Until hospital discharge, assessed up to 4 weeks
measure: Reintubation during index ICU admission
timeFrame: Until ICU discharge, typically within 28 days
measure: Tracheostomy during index ICU admission
timeFrame: Until ICU discharge, typically within 28 days
measure: Re-cannulation to ECLS during index ICU admission
timeFrame: Until ICU discharge, typically within 28 days
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: Daily, for duration of intervention
measure: Respiratory mechanics and gas exchange - Driving pressure.
timeFrame: Daily, for duration of intervention
measure: Respiratory mechanics and gas exchange - Pocc.
timeFrame: Daily, for duration of intervention
measure: Respiratory mechanics and gas exchange - P0.1
timeFrame: Daily, for duration of intervention
measure: Respiratory mechanics and gas exchange - plateau airway pressure
timeFrame: Daily, for duration of intervention
measure: Respiratory mechanics and gas exchange - P/F ratio
timeFrame: Daily, for duration of intervention
measure: Respiratory mechanics and gas exchange - ventilatory ratio
timeFrame: Daily, for duration of intervention
measure: Diaphragm thickness
timeFrame: Daily, for duration of intervention
measure: Maximal diaphragm thickening fraction
timeFrame: During first SBT
measure: Survival status at disconnection from mechanical ventilation (dead or alive)
timeFrame: Until day 28
measure: Organ failure-free days
timeFrame: Until day 28
measure: Serious adverse events (SAEs)
timeFrame: Throughout the trial
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: University Health Network
Study officials:
affiliation: University Health Network, Toronto
name: Ewan Goligher, MD, PhD
role: STUDY_CHAIR
affiliation: University Health Network, Toronto
name: Eddy Fan, MD, PhD
role: STUDY_CHAIR
affiliation: University Health Network, Toronto
name: Niall Ferguson, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Lorenzo Del Sorbo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Bram Rochwerg, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Unity Health Toronto
name: Bijan Teja, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Queens University
name: John Muscedere, MD
role: PRINCIPAL_INVESTIGATOR
References: