Clinical trial NCT04878510: Non-invasive Ventilation and Dex in Critically Ill Adults
Official title: Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults: a Vanguard Pragmatic Randomized Controlled Trial (inDEX Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Respiratory Insufficiency
Keywords: Non-Invasive Ventilation
Sedation
Randomized Control Trial
Acute Respiratory Failure
Lead sponsor: St. Joseph's Healthcare Hamilton
Sponsor class: OTHER
First posted: 2021-05-07
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The inDEX trial is a pragmatic, international, multi-centered, stratified, randomized, parallel-group, double-blind, placebo-controlled vanguard trial.
Primary purpose: TREATMENT

Brief summary: Non-Invasive ventilation (NIV) is a life saving intervention for patients with acute respiratory failure (ARF). Some patients are not able to tolerate the NIV intervention and ultimately fail, requiring the use of invasive mechanical ventilation (IMV) and intubation. Sedation may improve a patient's NIV tolerance. However, this practice has not been adopted by intensivists as the risk of over-sedation resulting in respiratory depression, inability to protect the airway, and inadvertent need for intubation are all large deterrents of sedative use in NIV.

The Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults: a Vanguard Pragmatic Randomized Controlled Trial (inDEX) is looking to evaluate the effectiveness of dexmedetomidine compared to placebo in reducing non-invasive ventilation failures in patients admitted to the hospital with acute respiratory failure. The results from this pilot trial, will subsequently inform a large, pragmatic, powered trial to definitively address the question.

Detailed description: 1. BACKGROUND:

   Non-invasive ventilation (NIV) is a life-saving intervention for patients with acute respiratory failure (ARF). Patients may find NIV intolerable and ultimately fail NIV requiring intubation and invasive mechanical ventilation (IMV). Sedation may improve a patient's NIV tolerance. However, this practice has not been adopted by intensivists as the risk of over-sedation resulting in respiratory depression, inability to protect the airway, and inadvertent need for intubation are all large deterrents of sedative use in NIV. Current guidelines lack recommendations on which sedative, if any at all, should be used during NIV due to the paucity of reliable data. Dexmedetomidine (dex) is a relatively new sedative. It promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and when compared to γ-aminobutyric acid receptor agonists like benzodiazepines, reduces delirium. Dex has been recommended to use over benzodiazepines for sedation during IMV in critically ill adults, particularly if delirium is precluding weaning.
2. HYPOTHESIS:

   We hypothesize that dexmedetomidine, when compared to placebo, reduces NIV failure in hospitalized adults with acute respiratory failure and agitation or NIV intolerance.
3. OBJECTIVES:

   To evaluate the feasibility of assessing if dexmedetomidine compared to placebo results in a reduction of non-invasive ventilation failure in patients admitted to the hospital with acute respiratory failure. This will subsequently inform a large, pragmatic, powered trial to definitively address the question.
4. METHODS

4.1 Study design: The inDEX trial is a pragmatic, international, multi-centered, stratified, randomized, parallel-group, double-blind, placebo-controlled vanguard trial. Patients, investigators, healthcare team, data collectors, outcome assessors, and the statistician will be blinded to trial arms.

4.2 Allocation and randomization: Local Research Coordinators (RC) will randomize eligible patients in a fixed 1:1 allocation using undisclosed variable block sizes of four, six, or eight. The randomization will be achieved using a random number sequence prepared by an independent statistician. The independent statistician will have access to the random number sequence and it will be provided to the research pharmacist. Upon request by the local research coordinator, the research pharmacist will provide the care team with either placebo or dexmedetomidine, according to the randomization schedule. 4.3 Blinding: Both dexmedetomidine and normal saline placebo will be given as continuous infusion. To minimize performance and ascertainment biases, and maintain blinding of patients, investigators, clinical staff, and RCs; a Research Pharmacist, who is not involved in assessment of patient outcomes or patient care, will prepare infusion bags. Titration of the infusion rate for both arms will follow an identical volume-based titration algorithm. Despite optimal blinding efforts, it is possible that the care team may be able to determine who is receiving dexmedetomidine based on improvement in NIV tolerance and/or the decrease in heart rate and blood pressure. However, the cointerventions may also improve tolerance, and can certainly cause a reduction in heart rate and blood pressure.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years
2. Patient receiving any NIV modality for acute respiratory failure of any etiology
3. Admitted to ICU, PACU, step-down unit (surgical or medical), or emergency department
4. Presence of one or more of the following after optimized NIV treatment

   1. Agitation (Defined as a Richmond Agitation and Sedation Scale \[RASS\] score of ≥+2 or a Riker Sedation-Agitation Scale \[SAS\] score of ≥5)
   2. Patient expresses intolerance or requests removal of NIV secondary to self-reported discomfort, anxiety, or claustrophobia
   3. Other reason that the physician feels the patient is intolerant of NIV or agitated, not captured above (all reasons will be recorded)

Exclusion Criteria:

1. Absence of a functioning pacemaker with one of the following: a-Persistent bradycardia defined as a heart rate (HR) ≤50bpm; b-Second or third-degree heart block; or c- Tachybrady syndrome
2. Persistent hypotension, defined as a mean arterial pressure (MAP) ≤60mmHg despite volume resuscitation and vasopressors
3. Acute hepatic failure
4. Known allergy to dexmedetomidine
5. Pregnancy
6. Acute withdrawal from drugs or alcohol
7. Patients with post-extubation respiratory failure
8. Imminent need for endotracheal intubation
9. Death is deemed imminent and inevitable
10. Patient's goals of care do not include intubation and IMV
11. Patients already on dexmedetomidine at time of enrollment
12. Previously enrolled in the inDEX trial
13. Treating physician refuses enrollment (reasons for refusal will be captured)

Primary outcomes:
measure: Recruitment Rate
timeFrame: At the completion of the trial (approximately 1 year).
measure: Protocol Adherence; Proportion of patients assigned to the experimental arm that received the intervention and those assigned to the control arm that did not receive the intervention.
timeFrame: At the completion of the trial (approximately 1 year).
measure: Consent Rate
timeFrame: At the completion of the trial (approximately 1 year).
Secondary outcomes:
measure: Acute care unit outcomes; Non-invasive ventilation (NIV) failure
timeFrame: 28 days post-randomization.
measure: Acute care unit outcomes; Acute Care Unite Length of Stay
timeFrame: 60 days post-randomization.
measure: Acute care unit outcomes; Duration of invasive mechanical ventilation
timeFrame: 60 days post-randomization.
measure: Acute care unit outcomes; Ventilation free Days
timeFrame: 28 days post-randomization.
measure: Process Outcomes; Number of patient-initiated device removal episodes.
timeFrame: 4 days post-randomization.
measure: Process Outcomes; Richmond-Agitation Sedation Scale (RASS) measurements
timeFrame: 4 days post-randomization.
measure: Process Outcomes; The mean NIV tolerance score.
timeFrame: 4 days post-randomization.
measure: Process Outcomes; Days spent with delirium
timeFrame: 28 days post-randomization.
measure: Process Outcomes; Cointerventions
timeFrame: 4 days post-randomization.
measure: Hospital Outcomes; Hospital length of stay
timeFrame: 60 days post-randomization.
measure: Hospital Outcomes; Mortality
timeFrame: 60 days post-randomization.
measure: Adverse Events: Bradycardia
timeFrame: 60 Days post-randomization
measure: Adverse Events: Severe bradycardia
timeFrame: 60 Days post-randomization
measure: Adverse Events: Clinically significant bradycardia
timeFrame: 60 Days post-randomization
measure: Adverse Events: hypotension
timeFrame: 60 Days post-randomization
measure: Adverse Events: clinically significant hypotension
timeFrame: 60 Days post-randomization
measure: Adverse Events: hypertension
timeFrame: 60 Days post-randomization
measure: Adverse Events: Cardiac Arrest
timeFrame: 60 Days post-randomization
measure: Functional Outcomes; quality of life
timeFrame: 60 Days post-randomization
measure: Functional Outcomes; clinical frailty
timeFrame: 60 Days post-randomization
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Monash Medical Centre - Monash Health
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City - Riyadh
Study officials:
affiliation: Research Institute of St Joseph's Healthcare Hamilton
name: Kimberley Lewis, MD
role: PRINCIPAL_INVESTIGATOR
References: