Platform of Randomized Adaptive Clinical Trials in Critical Illness

Study Overview
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Brief Summary
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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
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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.

Official Title
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Platform of Randomized Adaptive Clinical Trials in Critical Illness

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

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


Participation Criteria
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Eligibility Criteria
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PRACTICAL Platform Inclusion Criteria: Acute hypoxemic respiratory failure meeting all of the following criteria; New or worsening respiratory symptoms developing within 2 weeks prior to the onset of need for oxygen or respiratory support 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Ultra-protective ventilation facilitated by extracorporeal carbon dioxide removal (ULTIMATE) domain<br>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. | Other: Ultra-Protective Ventilation Facilitated by Extracorporeal Support<br>* Patients randomized to the intervention group will receive VV-ECMO with the ventilator set to minimize driving pressure and respiratory rate for ultra-protective ventilation.<br>Other: Lung-Protective Ventilation (LPV)<br>* Patients randomized to LPV will receive standard of care lung-protective ventilation with conventional limits on tidal volume and plateau airway pressure.<br>|
| Other: Invasive Mechanical Ventilation (IMV) Strategies domain<br>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. | Other: Lung-Protective Ventilation (LPV)<br>* Patients randomized to LPV will receive standard of care lung-protective ventilation with conventional limits on tidal volume and plateau airway pressure.<br>Other: Driving Pressure-Limited Ventilation (DPL)<br>* 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.<br>Other: Lung- and Diaphragm-Protective Ventilation and Sedation (LDPVS)<br>* Patients randomized to LDPVS will have ventilation and sedation adjusted to maintain lung-distending pressure and respiratory effort in a safe target range.<br>|
| Other: The Corticosteroid Early and Extended (CORT-E2) Randomized Controlled Trial domain<br>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. | Drug: Early Cohort corticosteroid dose<br>* 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.<br>Drug: Extended Cohort corticosteroid dose<br>* 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).<br>Drug: Usual care without routine corticosteroids<br>* Patients randomized to this arm will be managed according to usual care. They will receive corticosteroids only if prescribed by the clinician.<br>Drug: Usual care without extending corticosteroids<br>* Corticosteroids will stop after 10 days. Other management will be according to usual care. Patients will receive corticosteroids only if prescribed by the clinician.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 1 year of active site enrollment. | 
| IMV domain - ventilator-free days to day 28 in DPL vs LPV (DRIVE RCT) | 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. | Day 28 post randomization | 
| IMV domain - adherence to LDPVS management (LANDMARK RCT) | 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. | Day 28 | 
| IMV domain - probability of achieving and maintaining lung- and diaphragm-protective targets during mechanical ventilation (LANDMARK RCT) | 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. | Day 28 | 
| CORT-E2 domain - 60-day mortality from the day of randomization |  | Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 48 hours | 
| To measure and understand the reasons for crossovers in each group | 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. | 1 year | 
| Duration of mechanical ventilation during index ICU admission | Measured in CORT-E2, IMV, and ULTIMATE domains | Until ICU discharge, typically within 28 days | 
| Mortality at other endpoints | Measured in CORT-E2, IMV, and ULTIMATE domains | ICU discharge, hospital discharge, day 30, 180 days | 
| Duration of ICU admission | Measured in IMV and ULTIMATE domains | Until ICU discharge, typically within 28 days | 
| Hospital length of stay | Measured in CORT-E2, IMV domains | Until hospital discharge, assessed up to 4 weeks | 
| Discharge disposition. | Measured in IMV domain. Location to which patient is discharged (e.g., home, weaning facility, etc.) | Until hospital discharge, assessed up to 4 weeks | 
| Days alive and at home to day 90 | Measured in IMV domain | Day 90 | 
| Need for ICU readmission prior to hospital discharge | Measured in IMV domain | Until hospital discharge, assessed up to 4 weeks | 
| Duration of NIV | Measured in CORT-E2 domain | Until ICU discharge, typically within 28 days | 
| Duration of supplemental oxygen use | Measured in CORT-E2 domain | Until ICU discharge, typically within 28 days | 
| Need for ECLS | Measured in CORT-E2 domain | Until ICU discharge, typically within 28 days | 
| Duration of ECLS, only for patients who require ECLS | Measured in CORT-E2 domain | Until ICU discharge, typically within 28 days | 
| 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). | Measured in CORT-E2 and ULTIMATE domains. | Until day 30 for CORT-E2, and until day 28 for ULTIMATE | 
| EQ-5-D at day 180 | Measured in CORT-E2, IMV domains | Day 180 | 
| Complications from corticosteroids. | Measured in CORT-E2 domain. Hypernatremia, hyperglycemia, delirium, clinically important GI bleeding, nosocomial infection, neuromuscular weakness | Until hospital discharge, assessed up to 4 weeks | 
| Reintubation during index ICU admission | Measured in IMV domain | Until ICU discharge, typically within 28 days | 
| Tracheostomy during index ICU admission | Measured in IMV domain | Until ICU discharge, typically within 28 days | 
| Sequential Organ Failure Assessment (SOFA) score | Measured in IMV domain | Daily, for duration of intervention | 
| Respiratory mechanics and gas exchange - Driving pressure. | Measured in IMV domain. | Daily, for duration of intervention | 
| Respiratory mechanics and gas exchange - Pocc. | Measured in IMV domain. | Daily, for duration of intervention | 
| Respiratory mechanics and gas exchange - P0.1 | Measured in IMV domain. | Daily, for duration of intervention | 
| Respiratory mechanics and gas exchange - plateau airway pressure | Measured in IMV domain. | Daily, for duration of intervention | 
| Respiratory mechanics and gas exchange - P/F ratio | Measured in IMV domain. | Daily, for duration of intervention | 
| Respiratory mechanics and gas exchange - ventilatory ratio | Measured in IMV domain. | Daily, for duration of intervention | 
| Diaphragm thickness | Measured in IMV domain | Daily, for duration of intervention | 
| Maximal diaphragm thickening fraction | Measured in IMV domain | During first SBT | 
| Survival status at disconnection from mechanical ventilation (dead or alive) | Measured in ULTIMATE domain | Until day 28 |