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.

EXPAND-ECLS domain: The EXPAND-ECLS pilot trial is a multi-center, randomized, open-label, feasibility trial, embedded as a domain within the PRACTICAL platform trial. The ULTIMATE arm of 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. The PROACTIVE arm of this domain will evaluate the effect of ECMO-facilitated strategy of earlier awakening, extubation, and rehabilitation 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).

ESCAPE domain: Evaluating Subphenotypes in Immunocompromized Patients with ARF (ESCAPE) Domain is a prospective, multicentre observational cohort study, to identify subphenotypes across immunocompromised patients with acute hypoxemic respiratory failure (AHRF) using clinical characteristics and biomarkers. This study will prospectively collect biomarkers at the onset of AHRF which will allow us to characterize the underlying pathophysiology of AHRF with better precision.

WAVEFORM domain: The Clinical Implications of Potentially Injurious Patient-Ventilator Interactions (WAVEFORM domain) a prospective, multicentre observational cohort study, that aims at understanding the short- and long-term clinical consequences of longitudinal exposure to abnormal patient ventilation interactions in patients with AHRF, role of sedation as a mediator in this relationship. It aims at also exploring the heterogeneity of treatment effect of various mechanical ventilation strategies tested in the IMV based on the presence and burden of abnormal patient-ventilator interactions.

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 domain: 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 domain: 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.

IMPROV domain: The Inspiratory Muscle Training in Patients Receiving Ongoing Mechanical Ventilation is a pilot and feasibility RCT. It is designed to establish the feasibility of a definitive RCT of inspiratory muscle training to accelerate recovery from AHRF.

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

EXPAND-ECLS Domain Inclusion Criteria:

1. Receiving invasive Endotracheal mechanical ventilation for ≤ 72 hours.5 days
2. Early Moderate-severe hypoxemic respiratory failure with a PaO2/FiO2≤150200 mmHg for at least 6 hours

EXPAND-ECLS Domain Exclusion Criteria:

1. Patients over 70 years of age.
2. Currently receiving any form of ECLS (e.g., Venovenous, venoarterial, or hybrid configuration).
3. Chronic hypercapnic respiratory failure defined as PaCO2 > 60 mmHg in the outpatient setting.
4. Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BiPAP used solely for sleep-disordered breathing.
5. Actual body weight exceeding 1 kg per centimeter of height.
6. More than 48 hours have passed since meeting inclusion criteria.
7. Severe hypoxemia with PaO2/FiO2 < 80mmHg for > 6 hours at time of screening.
8. Severe hypercapnic respiratory failure with pH < 7.25 and PaCO2 > 60 mmHg for > 6 hours at time of screening.
9. Expected mechanical ventilation duration < 48 hours at time of screening.
10. Confirmed diffuse alveolar hemorrhage from vasculitis.
11. Contraindications to limited anticoagulation (e.g., active GI bleeding, bleeding diathesis).
12. Previous hypersensitivity/anaphylactic reaction to heparin or heparin-induced thrombocytopenia
13. Neurologic conditions at risk for or undergoing treatment for intracranial hypertension
14. Underlying illness with life expectancy < 1 year
15. Pregnancy (due to unknown effects of PaCO2 changes on placental blood flow)
16. 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
4. FOR STUDY SITES PARTICPATING IN THE EIT INTERVENTION: PaO2/FiO2 (if available) < 200 mm Hg at randomization. If PaO2/FiO2 has not been measured, SpO2 = 97% on FiO2 =60%.

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

FLUDRO Domain Inclusion Criteria 1. Within 72 hours of admission to an ICU

FLUDRO Domain Exclusion Criteria

1. Known hypersensitivity to fludrocortisone
2. An inability to receive fludrocortisone due to lack of enteral access
3. An indication to prescribe fludrocortisone for a reason that is unrelated to a current episode of pneumonia or acute respiratory failure, such as Addison's disease
4. Belief of the treating clinical team that study participation would not be in the best interest of the patient

FAST-3 Domain Inclusion Criteria (must meet all 3 of the following)

1. Patient is in a PRACTICAL eligible platform state and requires advanced respiratory support (ARS) defined as one of the following:

   a. Invasive mechanical ventilation with FiO2 > 40% b. Non-Invasive Ventilation (> 4 hours consecutively with FiO2 > 40%) defined as: i. CPAP or BiPAP (any settings or interface) ii. HFNC (flow > 40 liter per minute)

2. PaO2/FiO2 < 300 mm Hg or SpO2/FiO2 < 315 (if PaO2/FiO2 unavailable due to lack of arterial blood gas at the time of screening). For SpO2/FiO2, criteria are SpO2 ≤ 97% on FiO2 ≥ 40% on both of the 2 hours immediately preceding eligibility assessment. If an arterial blood gas can be obtained, then a PaO2/FiO2 ratio is preferable.

3. Patient commenced advanced respiratory support < 48 hours prior to randomization.

FAST-3 Domain Exclusion Criteria

1. Patient commenced advanced respiratory support > 48 hours to time of randomization.
2. Known history of severe chronic pulmonary disease e.g., pre-infection requirement for home oxygen therapy or presence of chronic hypercapnia (PaCO2 > 60 mmHg); mild - moderate disease is still eligible in the absence of chronic hypercapnia or need for chronic oxygen therapy.
3. Currently enrolled in another trial studying investigational anti-inflammatory therapy, excluding established treatments used in clinical practice such as corticosteroids.
4. Known allergy to furosemide or sulfonamide drugs. If the patient is allergic to sulfonamide drugs but has received in the past or is currently receiving furosemide without incident, they can be enrolled since cross-reactivity between furosemide and sulfonamide agents is rare.

ESCAPE Domain Inclusion Criteria

1. Patients with severe AHRF who have an underlying immunocompromised condition
2. Within 48 hours of fulfilling the AHRF inclusion criteria as well as PaO2/FiO2 <300 or a SaO2/FiO2 < 315 on non-invasive respiratory support (venturi mask, non-invasive ventilation or high flow nasal oxygen as per the FiO2 requirements above) or invasive ventilation.

Patients may be enrolled from the wards or ICU.

Immunocompromised patients include:

1. Any patients requiring long term (>30 days) corticosteroids (>20 mg/day),

2. Any patients receiving non-corticosteroid immunosuppressive medications within the prior 3 months,

3. Acquired or inherited immunodeficiency syndrome,

4. Recipients of solid organ transplant,

5. Active hematologic malignancy (diagnosis or receiving treatment within prior 6 months),

6. Active solid tumor (diagnosis or receiving treatment within the prior 6 months) or

7. Any patients who have undergone allogeneic or autologous hematopoietic cell transplant in the prior 6 months (HCT).

   ESCAPE Domain Exclusion Criteria

   1. Patients whom are deemed palliative.

   WAVEFORM Domain Inclusion Criteria

   1. Patient is intubated at the time of eligibility assessment.

   WAVEFORM Domain Exclusion Criteria

   1. PaO2/FiO2 >300 mm Hg or (S/F >250, if PaO2/FiO2 has not been measured) at the time of eligibility assessment.
   2. Duration of mechanical ventilation during current ICU admission is ≥72 hours.
   3. Receiving ECLS without continuous invasive mechanical ventilatory support.

   IMV-ECLS Domain Inclusion Criteria

   1. Patients with AHRF (as defined in platform inclusion criteria #1 above) who have been consented for cannulation for VV-ECLS or who have been initiated on VV-ECLS within 6 hours at the time of randomization

   IMV-ECLS Domain Exclusion Criteria 1. Patients receiving ECLS for the primary intention of extracorporeal CO2 removal 2. Patients expected to be liberated from ECLS within <24 hours 3. History of recent pneumothorax or pneumomediastinum (<3 months at the time of eligibility assessment/randomization) 4. Patients receiving ECLS for the primary intention of bridge to lung transplantation (at the time of eligibility assessment/randomization)

   IMPROV Domain Inclusion Criteria

   1. Patients receiving invasive mechanical ventilation for AHRF as defined by the PRACTICAL platform trial criteria above.
   2. Within 7 calendar days of intubation

   IMPROV Domain Exclusion Criteria

   1. Patient is expected to be liberated from mechanical ventilation within 24 hours
   2. Known or suspected 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. Known pneumothorax or pneumomediastinum without chest tube placement sustained during current ICU admission* (re-confirm immediately prior to randomization)
   5. Patient is admitted primarily for acute brain injury (stroke, traumatic brain injury, etc.)
   6. Previously diagnosed chronic neuromuscular disorder
   7. Patient has an implantable cardiac defibrillator or pacemaker
   8. Planned to be transferred to another hospital before ICU discharge
   9. Already receiving a regimen of inspiratory muscle training using external resistive device or diaphragm neurostimulation

While blinding of treatment allocation is an important mechanism for mitigating bias, the nature of acute hypoxemic respiratory failure and the complexity of interventions to be tested in PRACTICAL may make it difficult to blind treatment allocation in some cases. Blinded allocation will be implemented where possible.

Where possible, clinical outcomes will be collected by research personnel who are masked to randomized treatment assignment. Even where research personnel cannot be blinded to treatment assignment, bias arising will be mitigated by selection of relatively objective endpoints not easily influenced by knowledge of treatment assignment.