Open Actively Recruiting

Platform of Randomized Adaptive Clinical Trials in Critical Illness

About

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.

Primary Purpose

Treatment

Study Type

Interventional

Phase

Phase 2/Phase 3

Eligibility

Gender

All

Healthy Volunteers

Minimum Age

18 Years

Maximum Age

N/A

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

7. 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