Platform of Randomized Adaptive Clinical Trials in Critical Illness
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. 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.
• 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)
• Receiving invasive Endotracheal mechanical ventilation for ≤ 72 hours.5 days
• Early Moderate-severe hypoxemic respiratory failure with a PaO2/FiO2≤150200 mmHg for at least 6 hours
• 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
• 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%.
• Within 72 hours of admission to an ICU
• New unilateral or bilateral airspace disease
• 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
∙ 1\. Within 72 hours of admission to an ICU
• 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)
• 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.
• Patient commenced advanced respiratory support \< 48 hours prior to randomization.
• Patients with severe AHRF who have an underlying immunocompromised condition
• 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:
• Any patients requiring long term (\>30 days) corticosteroids (\>20 mg/day),
• Any patients receiving non-corticosteroid immunosuppressive medications within the prior 3 months,
• Acquired or inherited immunodeficiency syndrome,
• Recipients of solid organ transplant,
• Active hematologic malignancy (diagnosis or receiving treatment within prior 6 months),
• Active solid tumor (diagnosis or receiving treatment within the prior 6 months) or
• Any patients who have undergone allogeneic or autologous hematopoietic cell transplant in the prior 6 months (HCT).
• 1\. Patients receiving invasive mechanical ventilation for AHRF as defined by the PRACTICAL platform trial criteria above.
• 2\. Within 7 calendar days of intubation