Platform of Randomized Adaptive Clinical Trials in Critical Illness

21-5940

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).

2023-04-30

2024-12-31

2024-12-31

Recruiting

6250

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

{'studyType': 'INTERVENTIONAL', 'phases': ['NA'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'DOUBLE', 'maskingDescription': '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.\n\nWhere 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.', 'whoMasked': ['PARTICIPANT', 'OUTCOMES_ASSESSOR']}}, 'enrollmentInfo': {'count': 6250, 'type': 'ESTIMATED'}}

2024-05-16