PRACTICAL: Platform of Randomized Adaptive Clinical Trials in Critical Illness

Sponsor
Ewan Goligher (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05440851
Collaborator
University Health Network, Toronto (Other)
1,000
2
28

Study Details

Study Description

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

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.

Condition or Disease Intervention/Treatment Phase
  • Other: Ultra-protective ventilation facilitated by extracorporeal support
  • Other: Conventional lung-protective ventilation
N/A

Detailed Description

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
1000 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Outcomes Assessor)
Masking Description:
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.
Primary Purpose:
Treatment
Official Title:
Platform of Randomized Adaptive Clinical Trials in Critical Illness
Anticipated Study Start Date :
Sep 1, 2022
Anticipated Primary Completion Date :
Dec 31, 2023
Anticipated Study Completion Date :
Dec 31, 2024

Arms and Interventions

Arm Intervention/Treatment
Other: ULTIMATE domain: ultra-protective ventilation facilitated by extracorporeal carbon dioxide removal

Other: Ultra-protective ventilation facilitated by extracorporeal support
Patients randomized to the intervention group will receive VV-ECMO.

Other: Conventional lung-protective ventilation
Patients randomized to the control group will receive standard of care ventilation.

Other: Invasive mechanical ventilation domain

Other: Conventional lung-protective ventilation
Patients randomized to the control group will receive standard of care ventilation.

Outcome Measures

Primary Outcome Measures

  1. ULTIMATE - To 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. [1 year of active site 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.

Secondary Outcome Measures

  1. ULTIMATE - 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. [48 hours]

    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.

  2. ULTIMATE - To measure and understand the reasons for crossovers in each group [1 year]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
PRACTICAL Platform Inclusion Criteria:
  1. Acute hypoxemic respiratory failure meeting all of the following criteria;

  2. New or worsening respiratory symptoms developing within 2 weeks prior to the onset of need for oxygen or respiratory support

  3. 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

  4. 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

  5. Age ≥ 18 years

  6. 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

  • Ewan Goligher
  • University Health Network, Toronto

Investigators

  • Study Chair: Ewan Goligher, MD, PhD, University Health Network, Toronto
  • Study Chair: Eddy Fan, MD, PhD, University Health Network, Toronto
  • Principal Investigator: Niall Ferguson, MD, MSc, University Health Network, Toronto

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Ewan Goligher, Clinician-Scientist, University Health Network, Toronto
ClinicalTrials.gov Identifier:
NCT05440851
Other Study ID Numbers:
  • 21-5940
First Posted:
Jul 1, 2022
Last Update Posted:
Jul 1, 2022
Last Verified:
Jun 1, 2022
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jul 1, 2022